Pediatric Atopic Dermatitis

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Background

Atopic dermatitis (AD) is a chronically relapsing skin disorder with an immunologic basis.[1] The clinical presentation varies from mild to severe. In the worst cases, atopic dermatitis may interfere with normal growth and development. Treatment consists of adequate skin hydration, avoidance of allergenic precipitants, topical anti-inflammatory medications, systemic antihistamines, and antibiotic coverage of secondary infections.

Although often used interchangeably, the terms eczema and atopic dermatitis are not equivalent. Eczema is a reaction pattern with various causes and the most common pediatric cause is atopic dermatitis. Other causes of eczematous dermatitis include allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, nummular eczema, dyshidrotic eczema, asteatotic eczema, and lichen simplex chronicus. Eczematous reactions can be classified as acute, subacute, or chronic, depending on historical and physical characteristics.

The images below depict patients with atopic dermatitis.


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Typical atopic dermatitis on the face of an infant.


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Flexural involvement in childhood atopic dermatitis.

Pathophysiology

Clinically unaffected skin in patients with atopic dermatitis has increased numbers of T-helper type 2 (Th2) cells compared with skin in patients without atopic dermatitis. Increased levels of interleukin (IL)-4 and IL-13 (Th2 cytokines) are seen in acute atopic dermatitis skin lesions, whereas chronic atopic dermatitis lesions show increased expression of IL-5 (Th2 cytokine) and IL-12 and interferon (IFN)-γ (Th1 cytokines). Chronic atopic dermatitis lesions also exhibit greater eosinophil infiltration compared with skin in patients without atopic dermatitis.

IL-4 enhances differentiation of T-helper cells along the Th2 pathway, and IL-13 acts as a chemoattractant for Th2 cells to infiltrate atopic dermatitis lesions. IL-13 may also directly induce IL-5 expression and eosinophil infiltration, thereby facilitating the transition from acute lesions into chronic lesions.[2]

In addition, patients with atopic dermatitis appear to have significantly decreased levels of skin barrier molecules compared with normal controls. Ceramide lipids in the stratum corneum, which are responsible for water retention and permeability functions, and skin barrier proteins such as filaggrin are expressed at significantly lower levels in the skin of patients with atopic dermatitis compared with the skin of patients without atopic dermatitis.[2, 3]

Significant evidence favors the hygiene hypothesis for the development of atopic dermatitis. An inverse relationship is recognized between helminth infections and atopic dermatitis but no other pathogens.[4] In addition, early day care, endotoxin, unpasteurized farm milk, and animal exposure appear to be beneficial, likely because of a general increase in exposure to nonpathogenic microbes.

Epidemiology

Frequency

United States

Atopic dermatitis occurs in approximately 10-20% of children and 2% of adults.[2] Children with concurrent asthma or hayfever have a 30-50% incidence of developing atopic dermatitis.

International

Prevalence rates for atopic dermatitis in children over a 1-year period ranged from around 2% in Iran and China to about 20% in Australasia, England, and Scandinavia.[5] Interestingly, populations that migrate from areas of low prevalence to areas of higher prevalence have shown an increased incidence of atopic dermatitis, bolstering the idea of strong environmental influences in the development of atopic dermatitis.

Race

No clear racial predilections have been identified.

Sex

Males and females are affected with equal incidence and severity.

Age

Atopic dermatitis may occur in people of any age but often starts in infants aged 2-6 months. Ninety percent of patients with atopic dermatitis experience the onset of disease prior to age 5 years.[6] Seventy-five percent of individuals experience marked improvement in the severity of their atopic dermatitis by age 14 years; however, the remaining 25% continue to have significant relapses during their adult life. A recent study concluded that the prevalence of atopic dermatitis in children younger than 2 years was 18.6%.[7]

History

Diagnostic criteria for atopic dermatitis (AD) have been proposed by Hanifin and Rajka (1980) and largely adopted by the American Academy of Allergy, Asthma, and Immunology.[8] Appropriate cases must have at least 3 major characteristics and at least 3 minor characteristics.

Major characteristics include the following:

Minor characteristics are as follows:

Most children with atopic dermatitis relate a history notable for intense pruritus and dry skin. The quality of the pruritus is referred to as a spreading itch. Affected children often have a lowered itch threshold, resulting in increased levels of cutaneous reactivity in response to stimuli. Patients may succumb to a vicious itch-scratch-itch cycle, in which pruritus stimulates a bout of scratching. This, in turn, increases skin inflammation and triggers a greater sensation of itching, thus exacerbating flares.

Altered cell-mediated immunity has been noted in patients with atopic dermatitis; these patients exhibit both impaired skin barrier function and defects in skin innate immunity.[9] This is clinically observed as a history of repeated unusual cutaneous infections (eg, eczema herpeticum, warts, molluscum, dermatophytes).[10, 11]

Physical

Three classes of skin lesions are recognized.

Typical locations of lesions by age

Associated findings

Associated findings in atopic dermatitis include keratosis pilaris; accentuated palmar creases; lichenification; atopic pleats; allergic shiners; transverse nasal crease; pallor around the nose, mouth, and ears; white dermographism; cataracts; and keratoconus.

Keratosis pilaris, or plucked-chicken skin, consists of large cornified plugs in the upper part of hair follicles and produces a stippled appearance of the skin on the outer aspects of the arms and legs and on the buttocks and trunk.

Hyperlinear palms are usually present at birth and persist throughout life. These consist of an increased number of fine lines and accentuated markings on the palms.

Lichenification of the wrists, ankles, popliteal fossae, or antecubital fossae is characteristic of chronic atopic dermatitis. It is observed as thickened, leathery, hyperpigmented patches of skin with a deepening of normal skin creases.

Atopic pleats (also referred to as Morgan-Dennie folds, Morgan folds, Dennie pleats, or mongolian lines) are skin folds observed just below the lower lid of both eyes and are retained throughout life.

Allergic shiners are violet-gray infraorbital discolorations caused by underlying vascular stasis. Increased pressure on nasal and paranasal venous plexuses causes edema in these areas, leading to development of atopic pleats and allergic shiners.

A prominent transverse nasal crease is a common sign of concurrent allergic rhinitis and, along with allergic shiners and atopic pleats, may be a clue to the diagnosis of an atopic diathesis.

Dermographism is a normal reaction in 5% of the population. After a firm pointed instrument is stroked against the skin, the path of the instrument is observed as a red line followed by an erythematous flare that ultimately develops into a wheal. This response occurs within 3 minutes of the insult. White dermographism is a paradoxical reaction wherein the initial red line is replaced within 10 seconds by a white line and an absence of a wheal. This reaction can be observed in atopic dermatitis and allergic contact dermatitis.

Atopic cataracts affect 4-12% of patients with AD and occur much earlier in life than senile cataracts. They typically are bilateral, central, and shield-shaped, and they mature rapidly. Because patients generally are asymptomatic, diagnosis is usually made by slit lamp examination. Incidence of cataracts in atopic patients appears to be unrelated to the use of topical steroids.

Keratoconus is an elongation of the corneal surface that is thought to be caused by long-term eye rubbing and may be a degenerative change in the cornea. Keratoconus affects approximately 1% of children with atopic dermatitis and can generally be alleviated with the use of contact lenses.

Some advocate use a scoring system, the SCORAD (Index) is the best validated scoring system in atopic dermatitis.[12] The extent of disease is measured by "the rule of nines," applied on a front/back drawing of the patient's inflammatory lesions. They are graded from 0-100 on 6 items, including erythema, edema/papulation, excoriations, lichenification, oozing/crusts, and dryness, with each item evaluated on a scale from 0-3.

Causes

The etiology of atopic dermatitis appears to be linked both to genetic causes and to environmental agents.

The prevalence of atopic dermatitis in children with one affected parent is 60% and rises to nearly 80% for children of two affected parents. Additionally, nearly 40% of patients with newly diagnosed cases report a positive family history for atopic dermatitis in at least one first-degree relative. Children of parents with atopic dermatitis have an increased risk of developing atopic dermatitis by age 3 years.[13] Much higher concordance rates for atopic dermatitis are observed in monozygotic twins (77%) than in dizygotic twins (15%).[2]

Recent evidence has demonstrated a strong genetic predisposition towards the development of atopic dermatitis in patients with loss-of-function mutations in the gene that encodes the epidermal structural protein filaggrin (FLG). Filaggrin deficiency causes a significant defect in the normal epidermal barrier that allows for enhanced allergen absorption through the skin, resulting in a higher incidence of dermatitis. FLG gene mutations have been associated with a more severe atopic dermatitis phenotype, earlier onset of atopic dermatitis, increased levels of systemic allergen sensitivity, and a higher proportion of patients with atopic dermatitis who eventually develop asthma.[14]

In addition, the specific loss-of-function null mutation R501x in the filaggrin gene appears to confer a higher risk of developing eczema herpeticum, which is a rare but serious complication that requires treatment with antiviral medications.[15]

Prenatal risk factors for atopic dermatitis are under investigation. Term infants of mothers who had gestational diabetes during pregnancy had an almost 8-fold increase in the prevalence of atopic dermatitis by age 6 years. Interestingly, this relationship did not occur in preterm infants of mothers with gestational diabetes. The reasons for this discrepancy are yet to be determined.[16]

A retrospective study of 414 children and adolescents with atopic dermatitis suggested that prolonged obesity in early childhood may be a risk factor for atopic dermatitis; this advocated the concept that weight loss may facilitate prevention and treatment of childhood atopic dermatitis.[17]

Environmental allergens repeatedly have been shown to trigger exacerbations of atopic dermatitis in susceptible individuals. Contact irritants, climate, sweating, aeroallergens, microbial organisms, and stress/psyche commonly trigger exacerbations.

Contact irritants (eg, soaps, solvents, wool clothing, mechanical irritants, detergents, preservatives, perfumes) compromise the integument, creating inflammation, irritation, and a portal of entry for further environmental insult. These surface irritants, along with the macerative effects of sweating and the drying effects of low humidity, lower the pruritic threshold. A vicious cycle of itching and scratching ensues, in which added cutaneous damage caused by scratching further lowers the pruritic threshold and subsequently causes increased itching.

Aeroallergens (eg, house dust mite, molds, pollen, dander) induce peripheral eosinophilia and elevate serum IgE levels. These early effects lead to increased histamine release from IgE-activated mast cells and elevated activity of the T-helper cell–mediated immune system. The increased release of vascular mediators (eg, bradykinin, histamine, slow-reacting substance of anaphylaxis [SRS-A]) induces vasodilation, edema, and urticaria, which in turn stimulate pruritus and inflammatory cutaneous changes.

Microbial agents (eg, S aureus, Pityrosporum yeasts, Candida organisms, Trichophyton dermatophytes) act in 2 different ways to promote the flares of atopic dermatitis. The microorganisms directly invade the skin, creating local injury and inflammation, and they induce a systemic allergic response to specific antigens, causing a rise in serum IgE and enhanced activity of the immune system.

Nearly all patients with atopic dermatitis are colonized by S aureus on lesional skin. More than half of patients with atopic dermatitis are colonized by S aureus strains capable of producing superantigens. These patients can develop superantigen-specific IgE antibodies that activate inflammatory cells in the skin. Staphylococcal enterotoxin B is a superantigen known to upregulate IL-31 expression in skin. IL-31 has been shown to induce pruritus and skin lesions resembling atopic dermatitis in mice.[2] In addition, methicillin-resistant S aureus strains with reduced susceptibility to vancomycin are increasing worldwide and have been documented in atopic children.[18]

Specific IgE levels to Malassezia furfur have been correlated with atopic dermatitis severity in a subgroup of patients. These Malassezia -specific IgE antibodies have been shown to crossreact with autoantigens in atopic dermatitis skin.[2]

Food allergy is implicated as a cause in one third to one half of children with atopic dermatitis. Food allergens may be the initial trigger for IgE autoreactivity to epithelial autoantigens in young children with atopic dermatitis.[2] The most common food allergens in children are egg, soy, milk, wheat, fish, shellfish, and peanut, which together account for 90% of food-induced cases of atopic dermatitis in double-blind, placebo-controlled food challenges. Fortunately, many clinically significant food allergies self-resolve within the first 5 years of life, eliminating the need for long-term restrictive diets.

Stress may trigger atopic dermatitis at the sites of activated cutaneous nerve endings, possibly by the actions of substance P, vasoactive intestinal peptide (VIP), or via the adenyl cyclase–cyclic adenosine monophosphate (cAMP) system.

Atopic dermatitis is the result of a complex relationship between genetic predisposition and environmental exposures, including climate.[19] Atopic dermatitis prevalence was significantly lower with highest-quartile mean annual relative humidity, and with 2 other factors associated with increased UV exposure.

Laboratory Studies

Other Tests

Histologic Findings

Medical Care

Consultations

Consider consultation with an allergist/immunologist or dermatologist for the following conditions:

Diet

Whether breastfeeding can help prevent development of atopic dermatitis in children remains unclear. A clinical report from the American Academy of Pediatrics recommended exclusive breastfeeding as opposed to cow's milk formula feeding over the first 4 months of life to prevent development of atopic dermatitis in infants at high risk of developing atopy.[22] However, several studies have found no protective benefit of exclusive breastfeeding in the first 3-6 months of life.[23, 24]

Supplementation with extensively hydrolyzed formulas in infants at high risk of developing atopic dermatitis appeared to be more effective at preventing atopic dermatitis than supplementation with partially hydrolyzed formulas or cow's milk formulas.[22] However, partially hydrolyzed cow's milk formula may be beneficial in treating infants with mild-to-moderate atopic dermatitis during the first 6 months of their life without affecting their nutritional status.[25]

For children older than 5 years, nutritionally adequate elimination diets are the goal if double-blind placebo-controlled trials indicate a clinically significant food allergy. However, most skin tests, radioallergosorbent tests (RASTs), and enzyme-linked immunosorbent assays (ELISA) that reveal positive results against food allergens are not borne out to cause disease flares in clinical trials; thus, elimination diets are only rarely indicated.

Activity

Medication Summary

Topical corticosteroids are the mainstay of treatment of atopic dermatitis (AD). These medications reduce inflammation and pruritus primarily by inhibiting the transcriptional activity of various proinflammatory genes. Topical steroids should be applied only to areas of acute exacerbations, whereas emollients should be used over the remainder of the skin. The absorption of topical steroids is much better through hydrated skin; thus, the ideal time for application is in the first 3 minutes after a bath or shower. The various topical steroid formulations, in ascending order of occlusiveness, include lotions, creams, gels, and ointments.

Lotions contain water and may be drying because of the evaporative effect; thus, they are used mostly in scalp and beard areas where drying effects are not as problematic. Lotions containing alcohol may cause a burning sensation upon application, especially on skin with fissured or ulcerated areas. Lotions may contain preservatives, solubilizers, and fragrances that can irritate the skin.

Creams are generally well tolerated but are less moisturizing than ointments. Creams are popular for their nongreasy appearance on treated skin and are more convenient during hot weather because they cause less occlusion of eccrine sweat glands than ointments and gels. As with lotions, creams may contain preservatives, solubilizers, and fragrances that can irritate the skin.

Gels are highly occlusive, but the propylene glycol base is irritating to the skin and promotes dryness. Therefore, gels, similar to lotions, are used mostly in scalp and beard areas where the drying effects are not as problematic. They are very effective in the management of acute weeping or vesicular lesions of atopic dermatitis.

Ointments are the most moisturizing of the topical steroid vehicles, but their occlusiveness may not be well tolerated because of their interference with sweat gland function and resultant development of sweat retention dermatitis, especially in warm humid climates. Ointments are the preferred vehicle for thickened, lichenified plaques of atopic dermatitis.

Systemic corticosteroids have been used in severe chronic atopic dermatitis, but use has been limited in the pediatric population because of the risk of severe adverse effects associated with chronic usage, including growth retardation and immune suppression.

Oral antihistamines are effective as systemic antipruritics, sedatives, and mild anxiolytics. These are beneficial especially at nighttime because pruritus is usually worse at night. Commonly used oral antihistamines include diphenhydramine, hydroxyzine, and doxepin. Pramoxine is a topical antipruritic agent and can be found as Prax, Pramosone, or PrameGel.

Coal tar topical preparations have antipruritic and anti-inflammatory effects.[26] They work as disinfectants and astringents and help to correct abnormal keratinization by decreasing both epidermal proliferation and dermal infiltration. They are effective as second-line agents for subacute, chronic, and lichenified atopic dermatitis. Cosmetically acceptable preparations recently have been made available and include AquaTar, Estar, Fototar, PsoriGel, and Neutrogena T/Derm Tar Emollient. Tar shampoos, such as Neutrogena T-Gel, are effective for scalp involvement. Adverse effects may include folliculitis and photosensitivity.

Topical calcineurin inhibitors (eg, tacrolimus, pimecrolimus) are the newest class of topical medications for atopic dermatitis. These nonsteroidal immunomodulators act by down-regulating the mediator release or cytokine expression of various cells, including Th1 helper cells, Th2 helper cells, mast cells, eosinophils, keratinocytes, and Langerhans cells. Calcineurin inhibitors may be especially useful for treating face, groin, or axillary areas, where steroid-sparing treatments are preferred.

Systemic cyclosporine can dramatically reverse severe flares of atopic dermatitis. Because of the risk of severe adverse effects, this treatment should be limited in duration. Once control is obtained, alternative maintenance therapy should be instituted.

Experimental treatments for atopic dermatitis have included trials of gamma-interferon and IL-2; both are inhibitors of Th2 cell functions and have been promising. Oral mycophenolate mofetil, an inhibitor of purine synthesis, has also been shown to be an effective alternative form of treatment for severe disease. A small study of 6 patients with severe atopic dermatitis showed promising results for treatment with anti-CD20 monoclonal antibody (Rituximab).[27]

Some evidence suggests that the use of traditional Chinese medicine herb combinations may result in short-term improvements in SCORing of Atopic Dermatitis (SCORAD) index scores, quality of life scores, and topical steroid use.[28] However, larger trials to evaluate safety and long-term efficacy are needed.

Conflicting results have been reported regarding the use of probiotics (eg, Lactobacillus, Bifidobacterium) in preventing atopic dermatitis or in controlling symptoms in children.[28] A recent meta-analysis indicated that prenatal and postnatal probiotic supplementation may be helpful in preventing the development of atopic dermatitis in young children but does not appear to be effective in treating existing atopic dermatitis.[29] Further studies on the subject are needed prior to developing firm conclusions on the usefulness of this complementary medicinal treatment.

Hydrocortisone topical (Cortizone, Dermolate, Westcort)

Clinical Context:  Adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity.

Triamcinolone Topical (Kenalog)

Clinical Context:  It treats inflammatory dermatosis that is responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Flurandrenolide (Cordran Tape)

Clinical Context:  Intermediate-potency topical corticosteroid. Each square cm provides 4 mcg.

Class Summary

In older children and adolescents, treat mild cases of atopic dermatitis with a low-potency (class VI or VII) topical steroid twice a day to decrease inflammation. Examples include hydrocortisone cream or ointment, 1% and 2.5%. For moderate cases of atopic dermatitis, intermediate-potency steroids (class III, IV, V) may be used for brief periods (< 2 wk) to control an eczematous flare. Subsequently, low-potency steroids can be used to maintain remission. For severe cases of atopic dermatitis, pulse therapy with high-potency topical steroids (class II) or oral steroids may be beneficial in adolescents. Use only low-potency steroids on the face, axillae, groin, and intertriginous areas because of increased absorption and increased local steroid side effects.

For mild atopic dermatitis in infants, class VI or VII topical steroids should be effective. If the infant has more severe atopic dermatitis, a moderate-potency steroid can be prescribed for as long as 1 week and then tapered down to a lower-potency medication for maintenance therapy. In general, do not treat infants with topical steroids in the high-potency classes (class II or above) without a referral to a dermatologist.

Cordran tape is a corticosteroid-impregnated polyethylene film that enhances topical steroid penetration up to 100-fold. Occlusion of a topical steroid under plastic wrap seems to work equally well. These methods are especially useful for chronic lichenified plaques of atopic dermatitis.

In order to achieve a quick, complete remission of atopic dermatitis symptoms, adequate amounts of topical steroid must be used. Many patients initially use suboptimal amounts of topical steroid products, leading to poor control of their atopic dermatitis symptoms and ultimate discontinuation of their therapy. Approximately 30 grams of medication is needed to cover the entire surface area of an adult body. For children, the fingertip unit (FTU) has been shown to accurately measure an appropriate amount of medication. The FTU is defined as the amount of topical medication that will cover the child's index finger from the tip to the metacarpophalangeal joint. For topical steroids, 1 FTU covers the hand or groin, 2 FTUs cover the face or foot, 3 FTUs cover an arm, 6 FTUs cover a leg, and 14 FTUs cover the trunk.

Atopic dermatitis increases the risk of developing lymphoma (both Hodgkin disease and non-Hodgkin lymphoma). This risk correlates with increasing severity of disease. One study found an even higher risk of lymphoma in patients with atopic dermatitis treated with topical corticosteroids. The risk rose with increasing potency of the topical corticosteroid and with longer duration of use.[30]

Prednisone (Deltasone, Orasone)

Clinical Context:  Decreases inflammation by reversing increased capillary permeability and suppressing PMN activity.

Class Summary

Symptoms typically dramatically improve in the first few days of treatment with systemic steroids, only to be followed by an equally dramatic rebound flare after cessation of treatment. Tapering oral steroids over 10-14 days may mitigate this effect. In addition, an intensified focus on hydration with bathing and appropriate use of topical steroids should be emphasized to prevent rebound phenomena after discontinuation of systemic steroids.

Mupirocin topical cream or ointment (Bactroban)

Clinical Context:  Inhibits bacterial growth by inhibiting RNA and protein synthesis.

Cephalexin (Keflex, Keftab)

Clinical Context:  First-generation cephalosporin arrests bacterial growth by inhibiting bacterial cell wall synthesis. Bactericidal activity against rapidly growing organisms. Primary activity against skin flora.

Erythromycin (E.E.S., Erythrocin) or azithromycin (Zithromax)

Clinical Context:  Macrolide antibiotics that inhibit bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest. For treatment of staphylococcal and streptococcal infections.

Oxacillin or dicloxacillin

Clinical Context:  Bactericidal antibiotic that inhibits cell wall synthesis. Used in the treatment of infections caused by penicillinase-producing staphylococci. May be used to initiate therapy when a staphylococcal infection is suspected.

Amoxicillin and clavulanate (Augmentin)

Clinical Context:  Drug combination treats bacteria resistant to beta-lactam antibiotics. Base dosage regimen on amoxicillin content. Because of different amoxicillin-clavulanic acid ratios in 250-mg tab (250/125) versus 250-mg chewable tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Acyclovir (Zovirax)

Clinical Context:  Patients experience less pain and faster resolution of cutaneous lesions when used within 48 h of rash onset. May prevent recurrent outbreaks.

Ketoconazole (Nizoral)

Clinical Context:  Imidazole broad-spectrum antifungal agent. Inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

Class Summary

Antistaphylococcal antibiotics (eg, topical mupirocin or bacitracin, first-generation cephalosporins, macrolides, penicillinase-resistant extended-spectrum penicillins such as oxacillin or dicloxacillin if resistant strains of S aureus are encountered, amoxicillin-clavulanate) are helpful in secondary bacterial infections. Herpes simplex superinfections (eczema herpeticum) should be suspected if vesicles are present or if no improvement is observed with oral antibiotics. Tzanck smear of the base of vesicles is positive in 70% of cases. Treat with oral or intravenous acyclovir for 10 days. Varicella infections may become severe in the setting of atopic dermatitis, and early treatment with acyclovir is recommended. Counsel all children with atopic dermatitis as to the benefits of vaccination against varicella. Treat dermatophyte infections with topical or oral antifungals, such as topical ketoconazole cream or shampoo.

Pramoxine (Prax, PrameGel) or doxepin topical cream (Zonalon)

Clinical Context:  Pramoxine elicits anesthetic effect by blocking nerve conduction and impulses by inhibiting depolarization of neurons. Doxepin topical cream is a potent antihistamine and is indicated for pruritus.

Diphenhydramine (Benadryl), hydroxyzine (Vistaril), or doxepin (Sinequan)

Clinical Context:  For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Class Summary

Topical local anesthetics or antihistamines (topical or systemic) may be used to decrease pruritus.

Tacrolimus, topical (Protopic)

Clinical Context:  The mechanism of action of tacrolimus in atopic dermatitis is not known. This agent reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-α, all of which are involved in the early stages of T-cell activation. Additionally, this agent may inhibit the release of preformed mediators from skin mast cells and basophils, and it may downregulate the expression of FCeRI on Langerhans cells. Used for the short-term or intermittent long-term treatment of moderate-to-severe atopic dermatitis that is unresponsive to first-line therapies (eg, topical corticosteroids) or in cases where first-line therapies are not applicable. The manufacturer and FDA recommend that the smallest amount and lowest potency that is efficacious be used to achieve control of symptoms. It is available as an ointment in concentrations of 0.03% and 0.1%.

Pimecrolimus (Elidel cream)

Clinical Context:  First nonsteroid cream approved in the US for mild-to-moderate atopic dermatitis. Derived from ascomycin, a natural substance produced by fungus Streptomyces hygroscopicus var. ascomyceticus. This agent selectively inhibits production and release of inflammatory cytokines from activated T cells by binding to cytosolic immunophilin receptor macrophilin-12. The resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release. Cutaneous atrophy was not observed in clinical trials, a potential advantage over topical corticosteroids. This agent is indicated only after other treatment options have failed. Available as a 1% cream.

Cyclosporine (Sandimmune, Neoral)

Clinical Context:  Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions.

Class Summary

Topical tacrolimus ointment and pimecrolimus cream have both been shown to diminish pruritus and inflammation markedly within 3 days of initiating therapy and to have persistent effects for as long as 12 months. Several studies have documented the rapid and prolonged improvement in clinical severity scores in children and adults with a range of severity of atopic dermatitis. Research has shown the beneficial effect of topical calcineurin inhibitors in patients refractory to topical corticosteroid therapy.[31, 32] The most common adverse effect is a local burning sensation upon application, but this symptom tends to diminish after the first few days of use.

In January 2006, the Food and Drug Administration (FDA) approved a black box warning for tacrolimus and pimecrolimus topical medications. The warning emphasized the lack of long-term safety data and a possible link to malignancies. No causal link between these agents and the development of malignancies has been established. Long-term studies on the safety of these agents in humans are not yet available, and the black box warning was based on case reports in humans and on animal studies. An analysis of tacrolimus ointment use in patients with atopic dermatitis over 4 years did not show any increased risk of infections or cancer.[33] However, longer term studies (10 y of follow-up or longer) are needed before firm conclusions about these concerns can be reached.

Establishing the long-term safety profile of topical calcineurin inhibitors is of paramount importance because they appear to provide an effective alternative to topical corticosteroid treatment in certain patients. Furthermore, pimecrolimus has been shown to improve the epidermal skin barrier without the concurrent risk of local skin atrophy commonly seen with topical corticosteroid treatment.[34] Thus, pimecrolimus appears to be an attractive candidate for long-term use in either a therapeutic or preventative capacity.

At the present time, physicians are advised to use the following guidelines when prescribing topical immunomodulators such as tacrolimus and pimecrolimus:[35, 36]

Oral cyclosporine has proven beneficial in patients with severe atopic dermatitis refractory to treatment with topical steroids. Discontinuation of cyclosporine frequently results in rapid relapse of skin disease. Significant adverse effects (eg, nausea, abdominal discomfort, hypertrichosis, paresthesias, hypertension, hyperbilirubinemia, renal impairment) have diminished enthusiasm for this drug, especially with the advent of the topical immunomodulators mentioned above.

A small, nonrandomized, nonblinded study of 6 patients with severe atopic dermatitis showed significant improvement in skin symptoms within the first 4-8 weeks of treatment with Rituximab.[27] Larger, randomized controlled studies are needed to verify this finding.

Further Outpatient Care

Deterrence/Prevention

Prevention of acute flares and the subsequent development of chronic lesions of atopic dermatitis are indicators of successful treatment for this disease. Maintenance of adequate hydration of the stratum corneum, avoidance of known or probable allergens and irritants, rapid self-treatment with the proper class of topical steroids, and judicious use of complementary therapies (eg, antipruritics, stress relievers, antibiotics) are the cornerstones of ensuring a high quality of life unimpeded by the more severe aspects of this disease.

Nonspecific triggers of inflammation in patients with atopic dermatitis may include physical or chemical irritants. The following simple measures should be followed in daily life to reduce the frequency and severity of irritant-induced atopic dermatitis flares[37] :

Prenatal and postnatal probiotic supplementation may be helpful in preventing the development of atopic dermatitis in young children. In a recent meta-analysis, the most commonly studied probiotic was Lactobacillus rhamnosus GG.[29] Larger, randomized controlled studies are needed to confirm these initial findings.

A dog living in the home at the time of birth has been associated with a 50% decrease in the incidence of atopic dermatitis at age 3 years.[13] One study found that, at age 4 years, dog-sensitized children experienced less risk for eczema, whereas cat sensitization significantly increased the risk.[38]

Children with ichthyosis vulgaris should avoid neonatal cat exposure to prevent atopic dermatitis.[39]

Complications

The most common complication of atopic dermatitis is secondary infection.

Prognosis

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Kevin P Connelly, DO, Clinical Assistant Professor, Department of Pediatrics, Division of General Pediatrics and Emergency Care, Virginia Commonwealth University School of Medicine; Medical Director, Paws for Health Pet Visitation Program of the Richmond SPCA; Pediatric Emergency Physician, Emergency Consultants Inc, Chippenham Medical Center

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Disclosure: Nothing to disclose.

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Caroline C Spagnola, MD, to the development and writing of this article.

References

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Typical atopic dermatitis on the face of an infant.

Flexural involvement in childhood atopic dermatitis.

Typical atopic dermatitis on the face of an infant.

Flexural involvement in childhood atopic dermatitis.