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Atopic dermatitis

Atopic dermatitis, also referred to as eczema, is an itchy eruption of the skin. It's a long-lasting (chronic) condition that may be accompanied by asthma or hay fever. Atopic dermatitis is most often seen in infants and children, but it can continue into adulthood or first appear later in life. Although atopic dermatitis may affect virtually any area, it classically involves skin on the arms and behind the knees. It tends to flare periodically and then subside for a time, even up to several years. The exact cause of atopic dermatitis is unknown, but it may result from a malfunction in the body's immune system.

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Atopic Dermatitis: a Review of Recent Advances in the Field

Joseph Lam; Sheila F Friedlander

Pediatr Health. 2008;2(6):733-747. ©2008 Future Medicine Ltd.
Posted 02/12/2009


Abstract and Epidemiology

Abstract

Atopic dermatitis is increasing in prevalence and currently affects 15-30% of children in urban areas. Immune dysregulation and an impaired epidermal barrier are important factors in the pathogenesis of this disease. Pruritus and a chronic relapsing remitting course are hallmarks of the disorder, and sleep disturbance can occur in both the patient and family. Preventive interventions include exclusive breastfeeding in the first 4 months of life and withholding solid foods for 6 months. The avoidance of irritants and the use of emollients decrease flares. Topical corticosteroids remain the mainstay of therapy, and should be judiciously utilized. Excessive and inappropriate use must be avoided, as well as 'steroid phobia'. The topical calcineurin inhibitors can be useful adjuncts. Systemic therapies are available for severe disease, but carry risks of adverse effects.

Epidemiology

Atopic dermatitis (AD), or childhood eczema, is a chronic skin disorder that often occurs in association with allergic rhinitis and asthma (known as the atopic triad). The prevalence of AD differs between countries/regions. In industrialized countries, the prevalence of AD has at least doubled in the last three decades,[1-3] and it affects approximately 15-30% of children.[4] Conversely, in developing countries it has been reported to be less than 10%.[5] The lifetime prevalence is estimated to be between 10 and 20%.[6]

In 45% of children, the onset of AD occurs during the first 6 months of life. It occurs during the first year of life in 60% of patients and before the age of 5 years in at least 85% of affected individuals.[7] In those children with onset before the age of 2 years, 20% will have persisting manifestations of the disease, and an additional 17% will have intermittent symptoms by the age of 7 years.[8]

Pathogenesis

The pathomechanism of AD is still not completely understood, but the disorder appears to result from the complex interaction between various susceptibility genes, defects in skin barrier function, immunological responses, host and environmental factors and infectious agents.

Genetics & Atopic Dermatitis

The role of genetic factors in AD is suggested by the concordance of 77% in monozygotic twins and the greater probability of having AD if one or, even more so, if both parents are atopic.[9] Furthermore, several genetic analyses have identified different chromosome regions with a linkage to AD, including linkages for asthma,[10] psoriasis[11,12] and several single-gene Mendelian disorders, such as hyperimmunoglobulinemia E syndrome, Wiskott-Aldrich syndrome and Netherton syndrome.[13]

There have been other chromosomal loci and candidate genes associated with AD[14-17] that encode various immunomodulators, including costimulatory proteins (CD80 and CD86) involved in T-cell activation (3q21); IL-3, -4, -5 and -11, granulocyte-macrophage colony-stimulating factor (GM-CSF; 5q31-33) and the ß-subunit of the high-affinity IgE receptors (11q13).[18]

These genetic linkages have recently been reviewed in an article that highlights the search for disease-specific AD alleles as well as identifying overlapping genes associated with other allergic characteristics and disorder.[19] Several genes which have been identified reside on chromosome 5q31-33. These genes encode cytokines that control IgE synthesis and include IL-4, -5 and -13. Th2 cells elaborate these cytokines, which are thought to play an important role in the initiation of the AD inflammatory process. It is theorized that patients with AD possess an overactive Th2 cytokine immune response, which affects B-cell function and favors IgE production.[20] However, 20% of atopic patients never develop an increased IgE response, further complicating our understanding of the disease.

Immune dysregulation clearly plays a role in AD. Nonetheless, significant recent data suggest that the status of the skin barrier may also impact on disease expression.

The genetic basis for an impaired epidermal skin barrier in AD has been linked with loss-of-function mutations within the filaggrin (FLG) gene, which encodes a structural protein essential for skin-barrier formation. FLG mutations, when combined with other low-frequency mutations, have a significant impact on AD susceptibility.[21] This recent finding supports the crucial role of the skin barrier in preventing allergic sensitization.[21-23]

The discovery of the association of FLG mutations with atopic diseases followed insights into a common disorder of keratinization, ichthyosis vulgaris.

To date, the number of FLG mutations identified in European populations is 20 and, in Asian populations, an additional 17 mutations have been identified.[24] The combined allele frequency of the initial mutations translates into a carrier frequency of almost 10% in individuals of European ancestry.[25] This association is observed in a series of replication studies, making the FLG mutation a strong and consistent AD risk.[26] Overall, between 18 and 48% of all eczema collections carry FLG-null alleles.[27]

The FLG mutation findings were corroborated in two recent, large, population-based studies on more than 6700 English children[28] and 3000 German children,[29] in whom the two common FLG mutations R501X and 2282del4 and three rare variants were analyzed.

The future of AD genetics is exciting and novel approaches to gene identification include microarray studies of AD that allow the simultaneous measurement of transcript abundance for several thousand genes through hybridization of cRNA to immobilized oligonucleotide probes. Genome-wide linkage analyses using polymorphic DNA markers and single nucleotide polymorphisms offer possibilities for further fine-mapping association analyses.[30,31]

At present, four genome-wide linkage studies of AD have been performed in Caucasian populations.[11,32-34] A recent genome-wide linkage study of AD in an Asian population revealed novel loci on chromosomes 15q21 and 1q24 linked to AD.[35]


Skin Barrier Disfunction & Atopic Dermatitis

The epidermis of individuals with AD shows a decreased content of ceramides that probably affects both the barrier function and inflammatory responses of skin.[36] These lipids evolve from lamellar bodies, which are extruded from keratinocytes in the upper portion of the epithelium. The abnormal barrier function of atopic skin leads to increased transepidermal water loss and increased penetration of irritant, allergens and microbes. There are several recent studies with intriguing findings concerning the skin barrier.

Nagelkerken et al. present an exciting new animal model with transgenic expression of ApoC1 disrupting the lipid component of the skin barrier and resulting in a mouse with many of the clinical features of AD.[37] The model displays both gross and histologic features of AD, including pruritus and spongiosis, respectively, which are hallmark features of the condition in humans. Importantly, this model also responds to topical treatment with corticosteroids, suggesting its potential utility for studying the efficacy of novel therapies. Finally, the work with ApoC1 transgenic mice not only suggests that components of the lipid metabolism pathway are good candidates for identifying additional AD-susceptibility genes, but also represents an opportunity to manage and perhaps even prevent subsequent atopic disorders with barrier restoration.


Immunological Responses & Atopic Dermatitis

Langerhans cells and inflammatory dendritic epidermal cells (IDECs) play a predominant role in the initiation of the allergic immune response through the conversion of prime naive T cells into the T cell of the Th2 type; IL-4 plays an important role in this process as it stimulates both the conversion of naive T cells to Th2 cells, and is produced in high quantities by the Th2 subsets. Langerhans cells may possess high-affinity receptors for IgE on their surface, which avidly bind allergens, such as food, aeroallergens and microbial superantigens. Such linkage induces the release of chemotactic signals and recruitment of IDECs and T cells. Stimulation of high-affinity IgE receptor (FcεRI) on IDECs leads to the release of high amounts of proinflammatory signals, which contribute to allergic immune response.[38]

Cytokines and chemokines are key factors in the elaboration of AD. As previously mentioned, Th2 cytokines (IL-4, -5 and -13) mediate isotype switching to IgE synthesis and upregulate expression of adhesion molecules on endothelial cells.[39] The eosinophilic cationic protein and IL-16 are also elevated in the acute AD phase.[38] In chronic AD skin, Th2 cytokine IL-5, which is involved in eosinophil development and survival, predominates[39] as well as the Th1-dependent expressions of IL-12 and -18, GM-CSF, IFN-γ[40] and several remodeling-associated cytokines, such as IL-11, IL-17 and TGF-ß1.[41]

Other cytokines shown to be involved in acute and chronic AD skin lesions include increased expression of the novel eosinophil chemoattractants, eotaxin, monocyte chemotactic protein-4[42] and fractalkine, a chemokine expressed on activated vascular endothelial cells stimulated with IL-1, TNF-α or IFN-γ.[43]

This imbalance of Th1 and Th2 in AD may depend on polymorphisms in the IL-18 gene on peripheral mononuclear cells, which react after stimulation with superantigens through the upregulation of IL-18 and the downregulation of IL-12.[41]

A variety of pharmacophysiologic abnormalities have also been described. Leukocytes, and especially monocytes, from atopic patients demonstrate elevated phosphodiesterase activity, leading to decreased levels of cAMP and increased production of prostaglandin and IL-10, which inhibit Th1 function and enhance IgE production.[41]


Host & Environmental Factors Concerning Atopic Dermatitis

A controversy remains regarding the impact of reduced infection (the so-called hygiene hypothesis) on increasing rates of allergic disease in the industrialized world. Some believe that early stimulation of the Th1 immune arm through infections helps to suppress or inhibit the Th2 arm, thus decreasing the development of Th2-associated cytokines and AD. Although the hygiene hypothesis has gained significant credibility in some circles, causation has not been proved. Some prospective data support inverse relationships between AD and endotoxin exposure, early day care, and animal exposure, while other data suggest a positive association between AD and infections in early life.[44] Recent studies have not demonstrated a relationship between exposure to indoor aeroallergens in early life and subsequent eczema.[45] The lack of any clear exposure-disease relationship between allergens in early life and subsequent eczema argues against certain allergen exposures being a major factor causing eczema.


Staphylococcus aureus & Atopic Dermatits

Atopic dermatitis skin has been found to be deficient in antimicrobial peptides needed for host defense against bacteria, fungi and viruses.[46] Antimicrobial peptides such as the cathelicidins represent the first-line defense against many infections, and are produced by keratinocytes following attachment of appropriate bacterial, viral or fungal antigens to Toll-like receptors present on the keratinocyte surface. IL-4 is known to suppress production of cathelicidins, and it has been theorized that this is the etiology of decreased levels of cathelicidin in atopic patients, given that they possess elevated IL-4 levels. Given that cathelicidins possess significant antiviral activity, it is not surprising that AD patients are predisposed to eczema herpeticum.[47]

Most patients with AD are colonized with Staphylococcus aureus and experience exacerbation of their skin disease after infection with this organism.[48]

In contrast to a prevalence of a carrier state in 10% of nonatopic individuals, in patients with AD S. aureus is recovered from 93% of skin lesions, 76% of uninvolved (normal) skin and 79% of anterior nares tested.[49,50]

This occurs through a number of possible mechanisms. As mentioned previously, a paucity of cathelicidins leaves the skin more vulnerable to colonization or infection. Superantigens of S. aureus, such as staphylococcal enterotoxin, can cause defects in regulatory T-cell function and promote skin inflammation. Most patients with AD make specific IgE antibodies directed against staphylococcal superantigens, which correlate with skin disease severity.[51]

These superantigens can also induce corticosteroid resistance, thereby complicating response to therapy.[38] This lower sensitivity to topical medicine with superinfection has also been demonstrated with calcuneurin inhibitors.[52]


Other

High expressions of adhesion molecules, specifically, intercellular adhesion molecules -1 and -3, E-selectin and L-selectin in skin lesions of AD patients suggest that they may be additional factors in the pathogenesis of AD and may be of clinical relevance for the management of AD.[31]


Clinical Features

The association of pruritus and the chronic relapsing character of the disorder, along with age-specific morphology and distribution of lesions are the most important features of AD (see "Clinical Features of Atopic Dermatitis"). The extent of involvement may range from mild and limited, to generalized and severe. Sleep disturbance is a common occurrence in both the child and his family. AD may be divided into three phases based on the age of the patient and the distribution of lesions. These arbitrary divisions are listed as the infantile, childhood and adult forms. Infantile AD patients typically present with erythematous papules and papulovesicles on the cheeks, forehead or scalp, and are intensely pruritic. The childhood phase typically occurs between 2 years of age to puberty. In children, the eruption is characterized by dry, scaling erythematous papules and plaques and the formation of large lichenified plaques reflecting chronic disease. Predominant areas of involvement include the flexural folds, the face and neck, the upper arms and back and the dorsa of the hands, feet, fingers and toes. In adolescent and adult disease, the lesions persist over the flexors, hands, feet and head and neck areas with evolution into predominantly lichenified plaques.


Diagnosis

Although disease definition is perhaps the most fundamental step in any form of medical research, at least ten synonyms for AD were in widespread use up until the late 1970s. In response to this, Hanifin and Rajka proposed a number of diagnostic criteria based on their clinical experience.[53] These criteria represented an important milestone in some degree of comparability of individuals in subsequent hospital studies. However, they are less useful in epidemiological studies because of their complexity and unknown validity.

In view of the absence of a definition for atopic eczema with known validity and repeatability, nearly a decade later, Williams and colleagues coordinated a UK Working Party and refined Hanifin and Rajka's criteria for AD (see "The UK Working Party' s Diagnostic Criteria for Atopic Eczema").[54] In an independent validation study of children in a population setting, the criteria were shown to have a sensitivity and specificity of 85 and 96%, respectively, when compared with a dermatologist's diagnosis.[55]

This revised criteria have been validated in different clinical and geographical settings[55-58] and have been most extensively validated. Other validated criteria used are the Schultz-Larsen criteria, Diepgen criteria, Kang and Tien criteria and International Study of Asthma and Allergies in Childhood (ISAAC) criteria.[59]

Features that were helpful in discriminating cases of AD from controls were the classical distribution of the dermatitis, its chronic relapsing nature, dry skin and presence of infraorbital folds.[60]

Recently, Johansson and colleagues and the European Academy of Allergology and Clinical Immunology (EAACI) proposed a new term, atopic eczema/dermatitis syndrome (AEDS), which was divided into nonallergic and allergic types.[61] The latter referred to IgE-associated allergic AEDS and they referenced only the IgE-associated forms of the diseases as true AD. Controversy exists regarding this discrimination.


Interventions

Education

Educational programs help to empower patients and caregivers dealing with chronic diseases. Many trials have now demonstrated significant improvements in severity in all intervention groups compared with control groups.

Some of these include a 12-lesson educational program that described positive outcomes after 1 year, including diminished fear of topical corticosteroid (TC) cream use.[62] Furthermore, a recent German multicenter study involving 820 children with AD demonstrated statistically significant improvements in the severity score for AD (SCORAD) measurements, quality of life, scratching index and adherence to treatment.[63] In addition, a longitudinal randomized, controlled study demonstrated significant improvement in the AD scoring measure and significant improvement in quality of life scores in the group of children aged 5-16 years.[64]


Primary & Secondary Prevention

The idea of food avoidance in prevention of AD is based on the concept that delayed exposure or avoidance of antigens is a modifiable factor in AD. A number of controlled interventions have tested this hypothesis of primary prevention through the nutritional route.[39] However, the role of food avoidance in the prevention of AD and food allergy is becoming less clear as some recent studies demonstrate that the delayed introduction of certain allergenic solids may not prevent allergy and may increase risks. In fact, a recent case series of over 2500 infants demonstrated that a delayed introduction of cow milk products and other food products was associated with an increased risk of AD at 2 years of age.[65]

The impact of breastfeeding on the prevention of AD remains controverial. A recent meta-analysis suggests that the incidence of infantile AD is reduced by breastfeeding for a least 4 months,[66] and a 2001 meta-analysis of 18 prospective studies found a protective effect of exclusive breastfeeding for three studies with a stronger effect for infants with a family history of allergy.[67] This effect tends to disappear after 3 years of age and is seen primarily in children with a family history of atopy.[68]

Conversely, results from other observational birth cohort studies, case-control studies and one cluster randomized, intervention trial have generally failed to demonstrate a protective effect of breastfeeding on outcomes of AD.[69]

Clearly, more long-term prospective studies are necessary before a consensus about breastfeeding recommendations can be reached.

For those who are unable to breastfeed, it is hypothesized that hydrolyzed cow's milk formula, which consists of predigested peptides of whey and casein, may have a reduced capacity to induce IgE-mediated reactions while maintaining equivalent nutritional values as breastmilk. A large controlled study in high-risk infants using different partially and extensively hydrolyzed formulas for the first 6 months of life demonstrated that using the extensively hydrolyzed casein formula reduced AD in infants up to the third year of life.[70,71] However, exclusive breastfeeding or breastfeeding with the hydrolyzed formula is not enough to prevent the majority of cases of AD. In addition, there is no evidence to support the use of soy formula for preventing allergy.

Based on these data, the American Academy of Pediatrics consensus statement in 2008 concluded that infants at high risk for atopy would demonstrate benefit from exclusive breastfeeding for at least the first 4 months of life,[72] and an expert panel from the EAACI has recommended the delayed introduction of solid foods for 4-6 months in breastfed or formula-fed infants.[73]

However, on the basis of currently available evidence, the beneficial effects are less likely to apply to infants who are not at risk of developing atopy, and exclusive breastfeeding beyond 3-4 months does not appear to lead to any additional benefit in the incidence of atopic eczema.[74] Of significant importance, maternal dietary restrictions during pregnancy or lactation have not been shown to prevent atopic disease.

In those with established AD, the role of food is more controversial. Although sensitization to food allergens, such as cow's milk and hen's eggs, is associated with infantile AD[75] and related to disease severity and disease persistence,[40,76,77] only in a minority of those with food sensitization are food allergens of clinical relevance, as demonstrated by food challenge studies. Nevertheless, many experts recommend the use of hydrolyzed or amino acid-based formulas in those children with significant disease who are unresponsive to traditional skin-care interventions.[78,79]


Tertiary Prevention

Basic therapy of AD should emphasize optimal skin care, addressing the skin-barrier defect with regular use of emollients and skin hydration, along with identifying and avoiding specific and nonspecific trigger factors. The regular use of emollients is important for addressing the severe dryness of the skin associated with AD and, together with skin hydration, represents the mainstay of the general management of AD. Emollients should be applied continuously, even if no actual inflammatory skin lesions are apparent.


Treatment

Treatment is based on disease severity with basic therapy for solely dry skin, low-mid potency TCs and/or topical calcineurin inhibitors (TCIs) for mild-moderate AD, mid-high potency TCs and TCIs for moderate-severe AD, with systemic therapy reserved for recalcitrant, severe AD.

Topical Corticosteroids. Topical corticosteroids have been the mainstay of treatment for AD for several decades. In addition to reducing skin inflammation, treatment with TCs can contribute to a reduction of skin colonization with S. aureus and may minimize a further trigger factor of AD. Common sense dictates the use of the lowest potency steroid that is effective in controlling disease, and the discontinuation of steroid when the patient is clear. In addition, most practitioners avoid the use of moderate or high potency steroids on the face or in the intertriginous areas for any prolonged period. Prolonged therapy at any site can lead to adverse effects, such as atrophy, or untoward systemic effects if too much or too potent a steroid is utilized for too long a period. Conversely, ill-informed parents who exhibit steroid phobia and withhold appropriate treatment endanger their children's wellbeing as well. The practitioner must do his best to balance the need for appropriate therapy with the risk of excessive misuse. Patients should be counseled to contact their practitioner if treatment in excess of 2-4 weeks does not lead to improvement, or if prolonged therapy is required, so that treatment can be adjusted. Pulse therapy consisting of twice-weekly use of a moderate potency topical steroid (fluticasone) for prolonged periods has been evaluated and found to be efficacious and safe, and is a therapeutic option.[80] Although no reports of skin thinning or atrophy were observed clinically, it is known that even with hydrocortisone acetate, a decrease in skin collagen synthesis may be seen.[81]

Topical Calcineurin Inhibitors. Topical calcineurin inhibitors are a relatively new class of medications for the treatment of AD and have been approved for use in AD since 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy that work by inhibiting calcineurin, thus preventing the dephosphorylation activity of phosphatase and the production and release of inflammatory cytokines and T-cell proliferation.

In January of 2006, the US FDA issued a black box warning on these compounds mentioning possible concerns about the potential of increased long-term malignancy risk owing to systemic immunosuppression and recommended that TCIs not be used as first-line therapy. Safety concerns arose from a small number of reported malignancies, animal toxicology studies and the potential adverse effects (including immunosuppression and risk of lymphoma) observed in patients who received systemically (rather than topically) administered calcineurin inhibitors for the suppression of solid-organ transplant rejection.

However, much recently, collected data indicate that these effects do not occur with topical administration. Systemic levels following topical administration are at least tenfold lower than with oral administration. Furthermore, the small number of lymphomas reported to date in individuals exposed to TCI use are not consistent with the types seen in transplant patients or other immunosuppressed patients. In addition, no adverse effects on the immune system have been observed in clinical trials of TCIs in children with AD. Overall, TCIs have an established safety and efficacy profile as long-term maintenance therapy in children with AD.[82-84] TCIs have proven particularly useful for the treatment of sensitive areas of the body, such as the eyelids and intertriginous areas. They are also good options for second-line therapy in children who cannot be maintained on short-course intermittent TC therapy. The TCIs are not yet FDA approved for children below the age of 2 years.

Other options for moderate-severe disease are available, but involve more intensive time on the part of the family or an increased risk-benefit ratio for the patient. These include wet-wrap therapy, light therapy and systemic agents.

Wet-wrap Therapy. In the wet-wrap therapy, a damp layer of cotton dressing is used in combination with emollients or TCs. A dry layer of gauze or clothing is then placed on top of the damp items, and patients are encouraged to keep these dressings in place overnight, or continuously as needed. Some experts recommend the use of twice-weekly bleach baths consisting of a quarter cup of bleach in a half-full tub, followed by rinsing, prior to applying wet wraps; however, evidence-based data are lacking on the efficacy of this therapy. Wet-wrap therapy has been shown to be beneficial in cases of exacerbated AD skin lesions. A recent small study utilizing a new garment for (Tubifast™) for wet-wrap procedures demonstrated efficacy when used for 3 days.[85] However, large prospective studies evaluating the efficacy and safety profile of wet-wrap therapy are lacking.[85-87]

Narrow-band UVB Phototherapy. Phototherapy can be broadly defined as the use of photons for the treatment of disease without the addition of an exogenous photosensitizer. UVB radiation (280-320 nm) is the most biologically active radiation in sunlight and is mainly responsible for erythema after sun exposure. The use of narrow-band (NB) therapy for AD is believed to have a better safety profile and equal or superior efficacy to natural sunlight or UVB exposure.

The exact mechanism of action of NB-UVB in AD is unknown, although it has been shown to suppress the proinflammatory cytokines IL-12, IL-2, IFN-γ and TNF-α and to have antimicrobial effects.[88] It has also been theorized that it is effective through increased activity of cathelicidins, mediated by increased photoactivation of hydroxylated vitamin D3, a known stimulus of cathelicidin production.[89] Treatments are usually given three- to five-times a week. The most widely used initial dose is 70% of the predetermined minimal erythema dose.[90,91]

In 2004, an update and guidance on the use of NB-UVB recommended that there was good evidence to support the use of NB-UVB in chronic AD.[92] In children, however, there have been very few studies observing the effect of NB-UVB in AD.[93-95] A recent large retrospective review of children with severe eczema who had undergone NB-UVB demonstrated that complete clearance or minimal residual activity was achieved in 40% of these children, a good improvement was achieved in a further 23% and a moderate improvement in 26%. Overall, the treatment was well tolerated and the median length of remission was 3 months.[90]

Narrow-band UVB requires special equipment, is not available to all patients and is a generally unsuitable treatment for younger children. The short-term side effects of phototherapy are usually mild and consist of xerosis and erythema, partly owing to occasional overdosage. Another risk can be photoactivation of the herpes virus.

It is associated with, as yet, undetermined risks of cutaneous malignancy. The long-term skin cancer risk of NB-UVB is thought to be less than that of photochemotherapy with psoralen and UVA,[96] although there are no data to quantify the long-term risk of developing skin cancer in children undergoing NB-UVB. It must be emphasized that, to date, information about the long-term side effects of UV therapy is still not available and UV therapy should be restricted to adolescents who are older than 12 years, except in exceptional cases.

A prospective, randomized, controlled study that incorporates agreed validated scoring systems is required to determine the long-term benefit of NB-UVB used for treating AD in children.

Antibiotics. S. aureus colonization has long been recognized as a complicating issue in AD, with a high rate of colonization and a proportional correlation with AD severity. It is worth noting that treatment with topical steroids alone can decrease S. aureus colonization.[97] Systemic antibiotic treatment is indicated for widespread bacterial secondary infection (primarily S. aureus). First- or second-generation cephalosporins or semisynthetic penicillins administered for 7-10 days are usually effective. Community-acquired methicillin-resistant S. aureus has become an increasingly important therapeutic issue when treating abscesses, but does not appear to be as prevalent in secondarily infected AD patients. However, this possibility must be considered for unresponsive patients.

Antihistamines. The therapeutic value of first-generation antihistamines appears to reside principally in their sedative properties. They are useful as short-term adjuvants to topical when there is severe pruritus. However, nonsedating antihistamines appear to have only a very modest influence on atopic eczema.

Leukotriene Antagonists. Leukotriene antagonists (montelukast and zafirlukast) are useful for the treatment of asthma and allergic rhinitis. For the most part, however, they appear to have little success in severe AD.[98-100]


Systemic Immunosuppressants

Cyclosporin A. Cyclosporin (CSA) is an immunosuppressive and anti-inflammatory medication that inhibits calcineurin-dependent pathways leading to reduced levels of proinflammatory cytokines, such as IL-2 and IFN-γ. CSA has been shown to be highly effective and well tolerated in the short-term treatment of severe childhood AD.[101-105] A recent systematic review and meta-analysis of systemic CSA in patients with severe atopic eczema suggested that effectiveness of CSA is similar in adults and children, but tolerability might be better in children.[106]

The treatment can be performed in the form of a short- or long-term therapy with high-dose (3-5 mg/kg/day) or low-dose (2.5 mg/kg/day) administration. Short-course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.[104]

Despite the effectiveness of oral CSA in the treatment of AD, because of the possible side effects, particularly renal toxicity and hypertension, the use of CSA should be limited to patients with severe refractory disease. CSA, while an effective short-term treatment, is less suitable for longer-term use because it may cause nephrotoxicity, hypertension, hepatotoxicity, tremor, gingival hyperplasia as well as effects seen on bone mass.[107] Contraindications must be excluded, and blood pressure and laboratory parameters must be monitored closely.

Azathioprine. Azathioprine (Imuran®) is a well-known systemic immunosuppressive agent available since 1959 that affects purine nucleotide synthesis and is effective in severe recalcitrant AD. Over the last two decades, azathioprine has occasionally been used to treat severe atopic eczema, although almost exclusively in adults.

A recent retrospective review of its use in atopic eczema in children suggested that it can be very effective in severe refractory AD.[108,109]

Azathioprine has a number of side effects, including myelosuppression, hepatotoxicity, gastrointestinal disturbances, increased susceptibility to infections and a hypersensitivity reaction consisting of malaise, myalgia, fever, gastrointestinal symptoms and cutaneous eruptions that may include a maculopapular rash, urticaria, vasculitis, erythema multiforme or erythema nodosum.[110] Furthermore, there are concerns relating to a possible long-term increase in risk of malignancy in patients treated with azathioprine, mostly from data in children receiving azathioprine for renal transplantation.[111]

Since azathioprine is metabolized by the thiopurine methyltransferase (TPMT), a deficiency of this enzyme should be excluded before initiating oral immunosuppression with azathioprine. TPMT genotyping is recommended if azathioprine is to be used safely and effectively, as those who are most at risk of myelosuppression can be identified prior to starting treatment. TPMT activity is measured using peripheral red blood cell lysates.

The recommended dosage of azathioprine for dermatologic indications is 1-3 mg/kg/day, but should be determined based on TPMT levels.[109] One group has even successfully used azathioprine as a treatment for patients with partial TPMT deficiency and demonstrated rapid response with initial doses of half-standard doses (1.25 mg/kg).[108] A prospective pilot trial utilizing this agent is currently under way, and further data will hopefully be available in the future.

Mycophenolate Mofetil. Mycophenolate mofetil (MMF) is a safer, more bioavailable, esterified form of mycophenolic acid that functions by the inhibition of inosine monophosphate dehydrogenase,[112] a key enzyme in the de novo pathway of purine synthesis. This preferentially inhibits the proliferation of B and T lymphocytes, which lack a purine salvage pathway and, therefore, depend upon de novo production.

Nausea, vomiting, diarrhea and abdominal discomfort represent the most frequent side effects of MMF, occurring in 10-30% of patients.[113] Mild increases in serum levels of liver enzymes are occasionally observed[114] and viral (especially herpes simplex) and bacterial infections have been described in patients undergoing treatment with MMF. Significant bone marrow suppression is not common with MMF therapy but the long-term risk of malignancy is a concern.

In the only pediatric series of MMF in AD, initial doses of MMF ranged from 12 to 40 mg/kg/day divided twice daily and doses were titrated upwards until patients either achieved disease clearance or reached a dose of 75 mg/kg/day (with a 3 g daily maximum).

Of the 14 children treated, four (29%) cleared, four (29%) had an 'excellent' response, five (35%) had a 'good' response and one (7%) had an 'inadequate' response.[112]

Methotrexate. Methotrexate is a widely used and effective treatment for other inflammatory diseases, such as psoriasis and rheumatoid arthritis, with a few small, retrospective reports and one open-label, dose-ranging, prospective trial suggesting that it is a well-tolerated and effective treatment in adult AD.[115] It is generally a well-tolerated drug, although bone marrow suppression, gastrointestinal toxicity and liver function abnormalities are well documented.

However, published pediatric studies are still lacking, and until further trials confirm its safety and efficacy, this drug should not be considered as a first-line therapy.

Bioengineered Immunomodulators. Most of the new biologic approaches to AD aim at inhibiting components of the allergic inflammatory response, including cytokine modulation (e.g., TNF inhibitors), blockade of the inflammatory cell recruitment (e.g., chemokine-receptor antagonists and cutaneous lymphocyte-antigen inhibitors) and inhibition of T-cell activation (e.g., alefacept and efalizumab).

IgE-blocking antibody omalizumab (Xolair®) is a recombinant human monoclonal antibody that targets the C3ε domain of free IgE, blocking binding to its high-affinity receptor. As a result, IgE does not bind to mast cells and basophils and, therefore, these cells do not release their mediators.[116]

Omalizumab is indicated for use in adults and children older than 12 years with asthma and AD. Its role in dermatology and for AD is probably best directed toward patients who have high levels of IgE and in whom the IgE is an etiologic factor for their disease.[117,118] However, pediatric data on this medication are limited.

Rituximab, a synthesized monoclonal antibody to CD20 (a B-cell surface antigen) is another biologic that demonstrates promise in the treatment of severe AD.[118] Unfortunately, limited experience with other agents, such as etanercept, have failed to show significant efficacy in the pediatric population.[119]

 

Complementary & Alternative Medicine.

The lifetime prevalence of complementary and alternative medicine used by patients who have dermatologic diseases (including AD) ranges from 35 to 69%.[120] These treatments include natural health products, nutritional supplements, biomechanical therapies such as massage therapies and mind-body therapies.

Preliminary evidence from small, randomized controlled trials (RCTs) suggests that the use of traditional Chinese medicine herbs, massage and mind-body therapies may be beneficial in treating pediatric AD. Some recent trials have demonstrated an improved quality of life, lower eczema scores[121,122] and reduced TC usage[123] with traditional Chinese medicine, while others have shown no effect.[124] There have also been reports demonstrating success with topical honey[125] and homeopathy.[126]

However, the quality of evidence for these therapies is poor and many of these trials have small number of participants, no allocation and concealment information and high dropout rates. Furthermore, there is some evidence that these treatments are not entirely benign.

Reports of hypersensitivity reactions, liver toxicity, agranulocytosis, cardiomyopathy and respiratory distress syndrome after ingestion of Chinese teas have been documented.[127] Although properly prepared homeopathic products are considered to be relatively safe, a few reports document that the chronic use of homeopathic remedies containing mercury, iron or arsenic has caused the exacerbation of AD.[127]

Nutritional Supplements. Probiotics are nonpathogenic microbes, usually of the lactic acid-producing variety, which are used to improve or normalize the balance of gut microflora and are believed to have immune-regulating actions.

At least ten RCTs have evaluated the use of probiotics as treatment for AD summarized in a recent review,[128] and another three RCTs have evaluated probiotics for AD prophylaxis. Of the ten treatment trials, six reported positive effects and two of the three prophylaxis trials reported positive findings. Some studies involved mothers taking probiotics prenatally and postnatally while nursing, and several positive results represented secondary outcomes rather than primary ones. Accordingly, study results should be interpreted cautiously.

In healthy individuals, the use of probiotics is generally safe and when administered in appropriate doses, Lactobacillus acidophilus, Lactobacillus GG and Saccharomyces sp. appear to be safe for use in children. However, higher doses are found in supplemental probiotic forms. In addition, in severely debilitated and immunocompromised children, there have been case reports of aggravation of existing symptoms, pneumonia, septicemia and meningitis.[128]


Conclusion & Future Perspective (5-10 Years)

The prevention of allergic disease and allergies remain a key focus of research; however, as indicated by this article, a perplexing controversy remains regarding the impact of reduced infection (the so-called hygiene hypothesis) on increasing rates of allergic disease.

It appears that dietary manipulation of the mother pre- or post-natally has little effect on the incidence of AD in her progeny; however, exclusive breastfeeding for the first 4 months of life appears to decrease the risk of atopic disease. Solid foods should be withheld for the first 6 months, but there is no evidence for longer periods. Further investigation is required to determine if hydrolyzed or amino acid-based formulas have any effect on the incidence of atopic disease later in childhood and adolescence. In addition, it is unclear whether the modest effects of the use of extensively or partially hydrolyzed formulas in early childhood can be confirmed and are sustained. Such studies should also include a cost-benefit analysis of the use of the more expensive hydrolyzed formulas. It should be noted that the potential benefit of these formulas has only been documented in infants at risk of developing atopic disease. Additional studies are needed among unselected infants or infants at low risk.

Major advances in AD include the clinical relevance of skin infection and the presumed positive association with decreased skin cathelicidin levels in atopics. The identification of loss-of-function mutations in the FLG gene, which result in skin-barrier dysfunction demonstrate the importance of an intact cutaneous barrier. Many experts suggest that a disrupted skin barrier may predispose to allergen sensitization, which in turn leads to further allergic disease.

Experience will continue to grow with systemic immunosuppressants in childhood AD. MMF represents an appealing therapeutic alternative to systemic immunosuppressive agents with less favorable side-effect profiles than have traditionally been used to treat children with severe AD.

There is increasing interest in, and evidence for the efficacy of, immunotherapy and biologic immunomodulatory therapies.


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