Reduction of Trigger Factors
Reduction of trigger factors (e.g., harsh chemicals, detergents, and wool) and avoidance of occupations that require contact with trigger factors (e.g., hairdressing, nursing, and construction) can be helpful.35 Appropriate behaviors should be taught to patients and parents early during life, when habits are more easily formed.36,37
Bland Emollients
The use of mild, nonalkali soaps and frequent use of emollients are important elements in the long-term management of AD. Because moisture evaporating off the skin can trigger flares, bathing is sometimes discouraged. A better approach is the prompt application of an emollient such as petrolatum (finishing within 3 minutes of the end of the bath), which can serve to seal the moisture from the bath. Lotions and creams containing high amounts of water are usually inadequate, however, and can actually worsen AD. Products containing hydroxy acids, phenol, or urea can reduce dryness and scaling, but these can sting inflamed skin and should therefore be used with caution. Because of a specific reduction of ceramides in AD, a lotion that provides excess ceramides relative to other lipids has been shown to have a therapeutic advantage in AD.38 Bubble baths and scented salts and oils can be irritating. Scalp care should include a bland shampoo. Topical tar products, such as shampoos and bath solutions, and topical creams and lotions containing 5% to 10% liquor carbonis detergens can help. Baths, soaks, and compresses with Burow solution can ameliorate crusted, infected, eczematous patches. Cotton clothing, washed to remove finishing (which often releases formaldehyde), is preferable to wool or synthetics.
Corticosteroids
Topical corticosteroids are another mainstay of therapy. Application immediately after bathing improves cutaneous penetration.
Table 2 Differential Diagnosis of Atopic Dermatitis
|
Type |
Disorders |
|
Dermatitides |
Allergic contact dermatitis |
|
Dermatitis herpetiformis |
|
|
Irritant contact dermatitis (may be concomitant with atopic dermatitis) |
|
|
Nummular eczema |
|
|
Seborrheic dermatitis |
|
|
Ichthyoses Immunologic disorders |
Ichthyosis vulgaris |
|
Graft versus host disease |
|
|
HIV-associated dermatosis |
|
|
Hyperimmunoglobulinemia E syndrome |
|
|
Wiskott-Aldrich syndrome |
|
|
Infectious diseases |
Scabies Dermatophytosis |
|
Metabolic disorders |
Zinc deficiency |
|
Various inborn errors of metabolism |
|
|
Neoplastic disorders |
Cutaneous T cell lymphoma |
|
Rheumatologic disorders |
Dermatomyositis |
Lowering the risk of side effects with less potent preparations must be balanced against gaining control of a flare quickly with more potent preparations. Long-term use of inadequately potent topical corticosteroids may pose a greater risk of adverse effects than brief use of more potent agents followed by a rapid taper to bland emollients. Because steroid-induced cutaneous atrophy is a greater risk on the face, in intertriginous areas (e.g., groin, axillae, and inframammary folds), and under diapers, less potent steroids (e.g., hydrocortisone and desonide) should be used in these areas, and they should be used with particular caution. For the remainder of the body, midpotency preparations, such as 0.1% triamcinolone acetonide, are helpful. More potent ointments, such as fluocinonide and desoximeta-sone, are useful for lichenified plaques. Flurandrenolide tape is useful for nodular prurigo (so-called picker’s nodules) because it also physically protects the area from manipulation. For the scalp, solutions are preferred.
Systemic corticosteroids (e.g., prednisone, 20 to 80 mg/day orally) may be useful to treat severe, acute flares. Because of the risks of gastrointestinal, endocrine, skeletal, central nervous system, and cardiovascular complications, however, they should not be used more than twice yearly.
Calcineurin Inhibitors
The steroid-free topical calcineurin inhibitors, tacrolimus ointment and pimecrolimus cream, are effective alternatives to topical corticosteroids. These agents do not cause the skin atrophy associated with prolonged use of topical corticosteroids and, therefore, are useful for treating skin on the face and neck.
The macrolide antibiotic tacrolimus (formerly FK506) has been found to be effective in treating moderate to severe atopic dermatitis. The efficacy of tacrolimus has been shown in several randomized, controlled trials.39-41 The most common adverse side effects are skin burning, flulike symptoms, skin erythema, and headache.41 Topical tacrolimus is available in 0.1% and 0.03% concentrations. In children with moderate and severe AD, treatment with tacrolimus ointment (0.03%) was shown to be superior to conventional 1% hydrocortisone acetate.42
The ascomycin derivative pimecrolimus (ASM 981) cream is a cell-selective cytokine inhibitor that was specifically developed for treatment of inflammatory skin diseases. Its mechanism of action is similar to that of topical tacrolimus. Two independent randomized, multicenter studies found pimecrolimus to be effective in infants and children with AD.43 Another randomized, multicenter study found that pimecrolimus was effective in preventing AD flares, which reduced the need for topical corticos-teroids.44 In adults, pimecrolimus was found to be effective and well tolerated, and it reduced the incidence of AD flare.45
A meta-analysis of 16 trials involving more than 5,300 patients showed success rates of tacrolimus and pimecrolimus to be statistically similar; however, tacrolimus success rates were numerically higher than those of pimecrolimus, and tacrolimus was used in patients with more severe disease.46 The efficacy of these drugs must be balanced against a potential cancer risk. The Food and Drug Administration recently issued a warning that these drugs should be used only as directed and only after other eczema treatments have failed to work.47
Other Therapies
Antihistamines can sometimes be helpful in breaking the itch-scratch cycle in AD. Sedating antihistamines, such as hydroxy-zine and diphenhydramine, are particularly useful—especially when itching prevents sleep48; however, the sedative properties of antihistamines may limit their use in AD. Cetirizine, a sedating antihistamine, appears to be well tolerated in infants. A multinational, randomized, placebo-controlled trial examined the effects of long-term treatment with cetirizine on infants with AD; the drug proved to be safe, and it reduced the need for topical corticosteroids in patients with more severe disease.49 Nonsedating antihistamines such as fexofenadine and lorata-dine are less useful. Doxepin, a tricyclic antidepressant known to have antihistaminic effects, can be beneficial when applied topically in a 5% cream.50
Virtually every phototherapy regimen has been reported to ameliorate AD. Some patients cannot tolerate the heat generated by the equipment, however—particularly that used in UVB irradiation. In addition to UVB, the following can be beneficial: UVA, longwave UVA1, narrow-band UVB, UVA-UVB, and PUVA. Extracorporeal photochemotherapy (photopheresis) is reported to be effective therapy for recalcitrant disease.51 Phototherapies are expensive, and prolonged use of PUVA has been linked to an increased risk of melanoma.52 Although some patients may benefit from natural sunlight, the risk of sunburn and induction of malignancy by ultraviolet light must be considered.
Antimicrobials are obviously important for patients with infection. Less clear is whether antimicrobial agents can directly treat AD by reducing bacterial products thought to exacerbate the condition. Antistaphylococcal therapy has been advocated for use in patients with AD; however, a double-blind, placebo-controlled study of flucloxacillin did not show improvement in AD despite reduced bacterial counts.53 Ketoconazole, likewise, has been used; its success, however, may be the result of anti-inflammatory, rather than antifungal, effects.
More advanced therapeutic options exist for severe, recalcitrant AD. The altered expression of cytokines in AD [see Etiology and Pathogenesis, above] has led investigators to explore the use of interferon gamma. Clinical trials have demonstrated that for some patients, daily subcutaneous administration of interfer-on gamma is effective in reducing both signs and symptoms of AD5455 and that long-term treatment can maintain the benefit.56 However, moderate results and high costs make interferon gamma less viable as a treatment option.
Oral cyclosporine (2.5 to 5 mg/kg/day orally),57,58 methotrexate (15 to 25 mg/wk orally), and azathioprine (100 to 200 mg/day orally) can be used in severe,59 recalcitrant disease provided that patients are monitored for adverse effects specific to those agents.
Traditional Chinese herbal medicine has been found to be effective in the treatment of AD, both in children60 and in adults,61 although the efficacy of this treatment remains controversial.62 The mechanisms of action of these preparations are unclear. A small, randomized, placebo-controlled study found topical treatment with St. John’s wort to be significantly superior to placebo in patients with moderate AD.63 Although evening primrose oil has for many years been proposed to be effective in AD, a well-controlled study failed to show any benefit to patients taking either evening primrose oil or a combination of evening primrose oil and fish oil, as compared with those receiving placebo.64 Patients should be cautioned that herbal remedies are not risk free and may carry a potential for hepatotoxici-ty, cardiomyopathy, and other adverse effects; such remedies should be monitored, as should any other treatment. To avoid potential adverse drug reactions, physicians should identify any herbal remedies used by patients.65
Topical vitamin B12 was found to be significantly superior to placebo in reducing the extent and severity of AD in a randomized, multicenter phase III study66; however, larger trials are needed to establish the efficacy of this therapy. The cAMP phosphodi-esterase inhibitor cipamfylline in cream form has been shown to be more effective than placebo but significantly less effective than hydrocortisone cream in the treatment of AD.67 The importance of well-controlled studies to assess efficacy of treatments must be stressed because AD patients on the placebo arms of most controlled studies tend to show benefit, sometimes marked.
Ichthyoses
The ichthyoses are a group of diseases of cornification that are characterized by excessive scaling.68 Etiologies of the ichthyoses are diverse, including genetic defects of structural proteins and enzymes, as well as acquired forms. Only the major clinical variants will be discussed here.
Major variants
Ichthyosis Vulgaris
Ichthyosis vulgaris, the most common form of ichthyosis, is found in approximately one in 300 births. This autosomal dominant condition presents as dry skin with fine scaling. The extensor surfaces of extremities are the most commonly affected areas. Ichthyosis vulgaris can occur concomitantly with keratosis pilaris and can also be associated with AD. Age at onset is typically between 3 months and 12 months. Implicated etiologic factors include reduced filaggrin (filament-aggregating protein) and its precursor profilaggrin, whose normal functions are to allow for aggregation of keratin filaments and to serve as sources of compounds that hydrate the skin. The clinical severity of ichthyosis vulgaris correlates with the degree of reduction in fi-laggrin and profilaggrin. Another possible etiologic factor is the reduced activity of proteases that normally lead to dissociation of keratinocytes.69
X-Linked Ichthyosis
Recessive X-linked ichthyosis occurs in approximately one in 2,000 to one in 6,000 male infants. Although collodion membrane may be present at birth, the skin is usually normal, with fine scaling beginning at 1 to 3 weeks of life. Typically, the scales are thick and dark, giving the skin a dirty appearance. Extensor distribution—combined with involvement of the sides of the neck and preauricular skin and sparing the flexural areas—is typical. Steroid sulfatase deficiency is an etiologic factor, causing an increase in cholesterol sulfate and a decrease in cholesterol in the stratum corneum.70 The accumulated cholesterol sulfate may inhibit proteolysis—a process similar to the inhibition seen in ichthyosis vulgaris. Prenatal diagnosis is available, and gene therapy may be on the horizon.
Lamellar Ichthyosis
Lamellar ichthyosis occurs in one in 300,000 births. It is inherited in an autosomal recessive pattern. Collodion membrane may be present at birth but is then shed, revealing characteristic large, platelike scales. Erythroderma may be present, albeit difficult to discern because of the thickness of the scales. Ectropion is present in most patients and can give rise to ophthalmic complications. Lamellar ichthyosis is often caused by mutations in the gene encoding the enzyme transglutaminase 1.
Figure 3 Erythroderma (total body erythema) and extensive scaling are seen in this infant with congenital ichthyosiform erythroderma.
Congenital Ichthyosiform Erythroderma
Formerly, congenital ichthyosiform erythroderma [see Figure 3] was considered to be a variant of lamellar ichthyosis. Both are inherited as autosomal recessive traits, and collodion membrane may be present at birth in both conditions. Ectropion, eclabion (eversion of the lip), and erythroderma can also occur. Like patients with lamellar ichthyosis, patients with congenital ichthyosiform erythroderma may have platelike scales on the lower extremities, but scales are fine and white on other parts of the body. Also in contrast to lamellar ichthyosis, X-linked ichthyosis, and ichthyosis vulgaris—whose lesions are scaly because of an abnormal ability to desquamate (so-called retention hyperkeratoses)—the lesions of congenital ichthyosiform ery-throderma are scaly because of increased production of ker-atinocytes (so-called hyperproliferative ichthyosis).
Epidermolytic Hyperkeratosis
Epidermolytic hyperkeratosis (formerly called bullous congenital ichthyosiform erythroderma) is autosomal dominant in inheritance. The combinations of large blisters and erythema with denuded skin that appear at birth may be confused with epidermolysis bullosa, staphylococcal scalded skin syndrome, or toxic epidermal necrolysis. Several months to 1 year after birth, the blisters become less prominent, and thick, verrucous plaques comprising rows of hyperkeratotic ridges develop. Flexural skin is usually involved, but the disease can be more extensive. Bacterial colonization leads to a clinically significant foul odor. Abnormal keratin gene expression is the etiologic basis of this condition.71
Figure 4 This patient developed marked scaling (acquired ichthyosis) over a 6-month period. Investigation revealed non-Hodgkin lymphoma.
Acquired Ichthyosis
Acquired ichthyoses have been associated with numerous systemic diseases and medications. Although the onset of scaling is commonly a manifestation of dryness or ichthyosis vul-garis, patients with unusual manifestations or with severe or recalcitrant disease warrant further investigation. Endocrinop-athies (e.g., thyroid disease), autoimmune diseases, infectious diseases (e.g., HIV), and malignancies such as lymphomas [see Figure 4] and other carcinomas have been associated with the onset of ichthyosiform dermatosis.
Treatment
The standard therapy for the ichthyoses is emollients (e.g., petrolatum) and keratolytics (e.g., lactic acid with or without propylene glycol).72 Lactic acid should be used cautiously in neonates to avoid causing excess absorption. Oral retinoids (which require lipid monitoring) can be helpful, particularly in the management of X-linked ichthyosis, congenital ichthyosi-form erythroderma, and lamellar ichthyosis. Epidermolytic hy-perkeratosis is the most difficult of these conditions to treat because of the risk of blistering induced by therapeutic agents. Antimicrobial agents can be useful to reduce the odor caused by bacterial colonization.
