Dermatology

Atopic Dermatitis (Atopic Eczema)

Atopic Dermatitis (atopic eczema) [ICD-9-CM code 691, 691.8]

Are You Confident of the Diagnosis?

Atopic dermatitis (AD) is a chronic, relapsing, pruritic dermatosis that commonly presents in early infancy or childhood. Diagnosis depends on a careful history and physical examination.

What you should be alert for in the history

Onset occurs in the first year of life in approximately 60% of patients, with most developing signs and symptoms between the third and sixth month of life. Approximately 90% of patients develop the disease before 5 years of age. Patients with AD may have another atopic disorder such as asthma or allergic rhinitis, with the incidence of this multiple-atopy phenomenon increasing with age.

About 70% of AD patients will have a family history of atopy. Parents should be questioned regarding any family history of asthma, allergic rhinitis (hay fever) or AD. Absence of an atopic family history makes the diagnosis of AD less likely.

Three different clinical phases of AD have been described: infantile, childhood, and adulthood. Each phase has a typical distribution pattern and lesion morphology, through one phase may overlap with the next. The infantile phase occurs from infancy up to approximately 2-3 years of age, the childhood phase from approximately 2 years to puberty, and the adult phase from puberty onward.

Characteristic findings on physical examination

Infantile AD is commonly found on the cheeks and scalp ( Figure 1), though the wrists, extensor aspects of the legs, neck and periauricular areas are also commonly involved. Truncal involvement is common but the diaper area is usually spared. Lesions tend to be symmetric, scaly, erythematous patches, with weeping and crusting prominent in severe cases. There is often associated generalized xerosis. Chronic changes such as lichenification are not a prominent feature in this phase.

Figure 1.

Characteristic facial involvement in infantile atopic dermatitis.

Pruritus is prominent feature of AD. Infants may rub themselves against objects such as carpet or bedding, causing excoriation. Intense pruritus often leads to sleep disturbance and/or secondary infection.

Childhood AD favors the flexural surfaces of the extremities, in particular the antecubital and popliteal fossae (Figure 2, Figure 3). Other frequently involved sites include the neck, flexures of the wrist and ankle, and the creases between the thighs and buttocks. These lesions tend to be ill-defined, scaly, erythematous patches with or without crusting and excoriation (Figure 4). Lichenification becomes prominent and tends to be most evident at the wrists and ankles (Figure 5).

Figure 2.

Childhood atopic dermatitis favors the flexural surfaces, like the popliteal fossae.

Figure 3.

Childhood atopic dermatitis favors the flexural surfaces, like the antecubital fossae. See also Figure 3.

Figure 4.

Childhood atopic dermatitis with xerosis, superficial crusts, lichenification and excoriations.

Figure 5.

Lichenification of the hands seen in a patient with severe and chronic atopic dermatitis.

Parents often mistake postinflammatory hypo- or hyperpigmentation with scarring. Generally, AD lesions do not scar unless severe secondary infection develops, or lesions are severely excoriated. Pigmentary changes resolve weeks to months after the active inflammation resolves. Darkly pigmented children with AD commonly have “perifollicular accentuation,” where the lesions are more papular and follicular-based than those of classic AD.

Adult AD also involves the flexural areas of the extremities and can be focal or more diffuse. Chronic hand and foot dermatitis become prominent and may be the only manifestation of AD for some patients. Neck and facial involvement also tends to be more prominent, with some patients have severe periocular disease. Adults tend to have more scaling and less crusting than infants and children. In general, older patients have more chronic findings, such as lichenification, than younger patients.

Expected results of laboratory studies

Laboratory studies are not usually necessary, but may be helpful in select cases. Patients with AD can have elevated serum immunoglobulin E (IgE) levels but is not specific to AD. Elevated IgE levels can also be seen with asthma, allergies and hyperimmunoglobulin E syndrome. A normal IgE level does not rule out the diagnosis of atopic dermatitis because up to 20% of AD patients will have a normal serum IgE level.

Specific serum IgE testing can be used to assess sensitization and assist with diagnosis of food allergies if there is a history of an allergic reaction (i.e., anaphylaxis, acute urticaria, angioedema) to a particular food, but serum IgE testing alone is not adequate to diagnose food allergy.

Skin biopsy is rarely necessary because the diagnosis can generally be made through a thorough history and physical examination. In diagnostically challenging cases, a skin biopsy may be helpful in diagnosis. Acute atopic dermatitis has prominent epidermal edema that can lead to intraepidermal vesicle or bulla formation with perivascular and intraepidermal lymphocytes (Figure 6). If the lesion persists, spongiosis becomes less exuberant and vesicle formation is absent while the epidermis thickens.

Figure 6.

Acute spongiotic dermatitis. (Courtesy of Bryan Anderson, MD)

Chronic lesions have a markedly thickened epidermis with hypergranulosis and sparse inflammation and spongiosis. Skin biopsy can diagnose scabies through identification of mites, eggs, or fecal material. Periodic acid Schiff staining of skin biopsies can identify fungal hyphae in tinea corporis.

Diagnosis confirmation

The diagnosis of atopic dermatitis can be divided into essential, important, and associated features.

Essential features (must be present): pruritus; acute, subacute or chronic eczematous dermatitis of typical morphology and age-specific patterns with a chronic or relapsing history.

Important features (seen in most cases, adding support to the diagnosis): early age of onset, personal or family history of atopy, IgE reactivity, and xerosis.

Associated features (suggest the diagnosis of atopic dermatitis but are nonspecific): atypical vascular responses (i.e,, facial pallor, white dermatographism, delayed blanch response), keratosis pilaris, hyperlinear palms, ichthyosis, ocular/periorbital changes, other regional findings (i.e., perioral changes/periauricular lesions), perifollicular accentuation, lichenification, prurigo lesions.

The differential diagnosis for atopic dermatitis includes seborrheic dermatitis (differentiated by a greasy scale, involvement of the diaper area in infants and toddlers, and less prominent pruritus); scabies (a polymorphous eruption often with papules, nodules, pustules, or urticarial lesions in addition to eczematous lesions. Facial involvement is uncommon); allergic or irritant contact dermatitis (distinguished by a configuration suggesting an external source or history of a common inciting agent); psoriasis (differentiated by red, sharply demarcated papules and plaques often located on the scalp, lower back, extremities, and areas of trauma. Diaper involvement can be seen in infants); and tinea corporis.

Some rare disorders can present with an eczematous eruption similar to AD. Primary immunodeficiencies, such as severe combined immunodeficiency (SCID), can present with erythroderma (diffuse redness usually associated with scaling). These infants will usually have other signs of systemic illness such as failure to thrive, chronic diarrhea and/or recurrent infections.

Wiskott-Aldrich syndrome presents with an extremely pruritic, diffuse eczematous dermatitis that may be more hemorrhagic in appearance than atopic dermatitis because of an associated platelet abnormality. The dermatitis in patients with hyperimmunoglobulin E syndrome resembles atopic dermatitis but inflammatory facial papules may be the predominant morphology. Repeated fractures and retained primary teeth result from skeletal and dental anomalies. Very high levels of serum IgE (>2000 mg/dl) are seen with this disorder, although patients with severe atopic dermatitis may have equally high levels. DOC8 deficiency may appear similar to classic autosomal dominant hyper-IgE syndrome in early life, but it often has extensive and recurrent cutaneous viral infections, including herpes simplex virus (HSV), human papillomavirus (HPV), molluscum contagiosum virus (MSC), and varicella-zoster virus (VZV).

Who is at Risk for Developing this Disease?

In developed countries, 10% to 20% of children and 1% to 3% of adults are estimated to be affected by atopic dermatitis. Between 1997 and 2004, pediatric patients with AD (newborn to 18 years of age) accounted for an estimated 7.4 million office visits in the United States alone. Disease onset typically occurs by 1 year of age in approximately 60% of affected infants and by 5 years of age in approximately 85% of affected children.

As noted above, about 70% of atopic dermatitis patients will have a family history of atopy. A classic study by Cooke and van der Veer showed that children with one allergic parent develop allergy 50% of the time, increasing to 75% if both parents were allergic.

What is the Cause of the Disease?

Etiology

Atopic dermatitis results from a complex interplay of genetic, immune, metabolic, infectious, neuroendocrine, and environmental factors. The two hallmarks of atopic dermatitis are defects in the epidermal barrier function and cutaneous inflammation.

Pathophysiology

Defective epidermal barrier function results from the downregulation of cornified envelope genes such as filaggrin, reduced ceramide levels, increased levels of endogenous proteolytic enzymes, and enhanced transepidermal water loss. A lack of certain endogenous protease inhibitors, exogenous proteases from Staphylococcus aureus and house dust mites, and soaps and detergents that can raise the local pH and increase activity of endogenous proteases further damage barrier function.

Skin inflammation in atopic dermatitis is partially mediated, at least in part, by a complex, temporal-spatial expression of proinflammatory cytokines and chemokines. Expression of cytokines seems to differ for acute versus chronic AD. Acute AD is associated with the production of T-helper type 2 (Th2) cytokines, which mediate immunoglobulin isotype switching to IgE synthesis and upregulate expression of adhesion molecules on endothelial cells. Increased levels of IL-17 induce the release of proinflammatory mediators from macrophages and fibroblasts.

In contrast, chronic AD lesions are associated with IL-5, which is involved in eosinophil development and survival, production of the Th1-like cytokines IL-12 and IL-18, and several remodeling-associated cytokines such as IL-11 and transforming growth factor β1. Research on the complex immunology of AD will provide additional insight into the disease.

Systemic Implications and Complications

Referral to immunology to evaluate for an underlying immunodeficiency should be considered if underlying systemic infections are frequent. In young children with atopic dermatitis and failure to thrive, referral to gastroenterology is warranted to evaluate for eosinophilic gastroenteritis/esophagitis.

Referral to ophthalmology should be considered in patients with chronic and severe AD. Cataracts and keratoconus (abnormally shaped cornea) have been described in AD and thought to be caused by chronic rubbing in response to inflammation. Cataracts tend to occur in older patients, generally in association with more severe cases of atopic dermatitis. Keratoconus occurs infrequently and in very severe cases.

Treatment Options

Treatment options are listed in Table I.

Table I.

Treatment options for atopic dermatitus
Medical Treatment Surgical Procedures Physical Modalities
Education and dry skin care
Emollients/Moisturizers
Topical
CorticosteroidsWet wrapsBleach bathsCalcineurin inhibitorsBarrier repair products
Phototherapy
Systemic
AntihistaminesAntimicrobialsAzathioprineCyclosporineMethotrexateMycophenolate mofetilSystemic steroidsProbiotics

Optimal Therapeutic Approach for this Disease

A successful treatment plan considers the patient’s age and needs, the extent and localization of AD at presentation, and the overall disease course, including previous response to treatment, disease persistence, frequency of flares, and susceptibility to and past history of infection. A comprehensive long-term strategy that encompasses education, trigger avoidance, excellent skin care, and treatment (medical and physical interventions) is vital.

Dry skin care education is the cornerstone of atopic dermatitis management. With little evidence to recommend the use of one emollient/moisturizer over another, patient and caregiver preference should drive product selection. Preparations that contain topical sensitizers (eg, fragrance, neomycin, benzocaine, etc) should be avoided.

The value of bathing and the frequency with which it should be undertaken remains controversial, though recent data suggest that the frequency of application of emollients/moisturizers may be more important than the timing of application to coincide strictly with bathing (the traditional "soak and seal" approach).

Topical corticosteroids remain first-line therapy for inflammation and pruritus. Variation in corticosteroid-prescribing habits (e.g., quantity, frequency, and duration of therapy) is common. Treatment depends on the location and severity of the AD.

A common initial regimen includes twice daily application of triamcinolone 0.1% ointment to the body, hydrocortisone 2.5% ointment to the face, axilla, and groin, and fluocinolone solution to the scalp until lesions clear. For younger children with mild but diffuse involvement, fluocinolone oil has a convenient vehicle for application of a low strength topical steroid to large areas

Wet wraps, commonly utilizing corticosteroids applied to wet skin and covered with wet gauze or clothing, are a useful tool to intensify treatment of severe AD and/or disease that is refractory to standard topical therapies. They may increase skin hydration, serve as an effective mechanical barrier to scratching, and act as an occlusive layer that promotes penetration of topical corticosteroids into the skin, thereby increasing the amount of medication delivered to the most severely affected areas. Wet wrap use should be closely supervised by a physician because of the concern for temporary systemic bioactivity of the corticosteroids.

The antiseptic properties of diluted bleach baths may help reduce the number of local skin infections and the need for systemic antibiotics in atopic dermatitis patients with heavily colonized and/or superinfected skin. A bleach bath can be prepared by mixing one-quarter to one-half a cup of sodium hypochlorite 6% solution (chlorine liquid bleach) in a bath tub full of lukewarm water or by use of commercial products with similar compositions. Once to twice weekly bleach baths can help decrease the frequency of skin infections in patients with chronic moderate to severe disease.

Topical calcineurin inhibitors are second-line therapy. Patients who may benefit include those with disease persistence and/or frequent flares or steroid tachyphylaxis. Topical corticosteroids steroids can often be used to treat flares and patients with a history of flare recurrence after discontinuation or tapering of topical corticosteroids may benefit from transition to a topical calcineurin inhibitor (TCI)therapy after achieving control. TCIs are also indicated in sensitive or thin skin areas, such as around the eye, face, neck, and genital area. TCIs may be used (off-label in the United States) proactively on an intermittent basis (eg, 2-3 times a week) to skin areas that otherwise would frequently flare.

Some studies have indicated that tacrolimus has better efficacy compared to pimecrolimus. Long-term safety and efficacy studies have shown a low incidence of side effects without significant evidence that TCIs are associated with systemic immunosuppression or increase for skin cancer. In most countries the use of TCIs is not recommended in patients under 2 years of age. Tacrolimus 0.03% is approved for use in children 2 to 15 years, and 0.1% for those 15 years and above.

Several novel barrier repair products that contain ingredients that may help to replace abnormal epidermal lipids, improve skin hydration, reduce skin barrier dysfunction, and relieve the pruritus, burning, and pain associated with AD are available. Products approved by the Federal Drug Administration for marketing as "501(k) Medical Devices" include MimyX, Atopiclair, EpiCeram, and Hylatopic. The high cost and small dispensed volumes limit their utility in the treatment of widespread AD, and studies have been inconsistent about the benefits of these products as compared to OTC emollients.

Sedating systemic antihistamines, such as diphenhydramine or hydroxyzine, do not appear to have direct effects on pruritus, but may be useful in improving sleep in flaring patients. Second-generation antihistamines, such as cetirizine, are less useful but may benefit patients with allergic triggers and chronic use may reduce the rate of progression to other atopic disease.

Importantly, topical antihistamines are not recommended because of potential cutaneous sensitization. Oral doxepin hydrochloride has a high H1- and H2-histamine receptor antagonist activity, but should only be used in severe cases because of the risk of sedation, hypotension, and depression/suicide.

Oral antibiotics should be used to treat clinical infection, but may be beneficial for sudden and severe flares of AD. Overgrowth of S. aureus can cause sudden exacerbations of AD independent of clinical signs of bacterial infection. Skin cultures and sensitivity testing should be considered prior to treatment.

Initial treatment should be with cephalexin, which is preferred over dicloxacillin because of its more convenient twice daily dosing. If there is a history of methicillin resistant S. aureus, MRSA, then clindamycin or trimethoprim-sulfamethoxazole should be considered. Recurrent, deep-seated S. aureus infections should raise the possibility of an immunodeficiency syndrome such as hyper-IgE syndrome.

Phototherapy is thought to suppress proinflammatory cytokines found in AD and induce T-cell apoptosis. Broadband ultraviolet (UV) B, broadband UVA, narrowband UVB (311 nm), UVA-1 (340–400 nm), and combined UVA-B phototherapy have been reported to be useful for widespread or recalcitrant disease, with narrowband UVB being the most commonly used modality.

Systemic therapy should be considered in patients with severe AD that does not respond to appropriate use of topical treatments. Selection of a systemic agent depends on a discussion of the risks and benefits of each treatment with the patient and/or family.

Azathioprine can be effective monotherapy for severe AD. Marrow suppression and liver toxicity are major concerns, and blood cell counts and liver function tests should be monitored closely. Azathioprine should be dosed according to thiopurine methyltransferase (TPMT) genotype/levels because low activity correlates with higher risk of marrow suppression.

Cyclosporine may be used as a short-term treatment or as a bridge between other steroid-sparing alternatives. A response may be seen in 2–3 weeks. Flares can occur after discontinuation of therapy, so gradual tapering is recommended. The safety and efficacy of cyclosporine are well documented in both adults and children. Hypertension, renal toxicity, and the risk of malignancy are limitations to long-term therapy.

Continuous therapy is not recommended beyond 1 year, and it is unknown how many short courses may be given safely. Blood pressure, CBC, renal and hepatic function tests, magnesium, and uric acid should be monitored regularly. Cyclosporine is typically dosed at 2.5–5 mg/kg/day. Dosing of cyclosporine microemulsion is 3 mg/kg/day in children, or 150 mg to 300 mg in adults.

The greatest advantage of methotrexate is that, at the relatively low doses used for skin disease it appears less immunosuppressive than other systemic therapies. Nausea and liver function abnormalities/hepatotoxicity may limit dosing. Pulmonary toxicity may be another potential concern. A response plateau is seen around 12 weeks with dosing of 0.5-0.8 mg/kg/wk, with little additional improvement at doses greater than 15 mg weekly.

Mycophenolate mofetil (MMF) has a good safety profile. Patients should be monitored for leukopenia and anemia, and drug levels may be increased in the setting of renal insufficiency. MMF has been loosely linked to herpes retinitis, dose-related bone marrow suppression, and increased infection (S. aureus). Younger children should be treated with 40–50 mg/kg/day in younger children, presumably due to increased surface area-to-volume ratios, and adolescents at 30–40 mg/kg/day. Maximal effect can be seen after 8–12 weeks of therapy.

The temptation to use systemic corticosteroids can be great, given the dramatic clinical improvement that can occur. The propensity to flare with abrupt discontinuation of treatment and the well-known associated systemic side-effect profile, however, suggest that systemic corticosteroids should be reserved for "crisis cases" – and even then used with the intent to bridge to another systemic agent or phototherapy.

Patient Management

A thorough explanation of the natural history of atopic dermatitis at the time of diagnosis can help mitigate some of the frustration patients and parents often experience. Providing a clear treatment plan for maintenance and flares can help decrease the frequency of severe flares.

Some clinicians start treatment with high-potency topical corticosteroid preparations in order to induce remission, followed by a relatively quick tapering-down of potency as the skin improves. Other clinicians use short bursts of high-potency corticosteroids followed by moisturizer use only until relapse occurs. Other treatment regimens utilize more prolonged continuous treatment with less potent preparations, and/or utilize non-steroidal agents, such as topical calcineurin inhibitors, applied intermittently (e.g., 2-3 times a week).

Families often wonder if food allergies contribute to AD. Guidelines for the diagnosis and management of food allergies were released in 2011 by an NIAID sponsored expert panel and set forth clear recommendations on when food allergies should be considered.

Children under the age of 5 years with moderate to severe AD that persists despite optimal therapy or with a history of a food allergy should then be tested for food allergies to milk, egg, peanut, wheat, and soy. Importantly, allergen-specific serum IgE (RAST) testing alone is not adequate to diagnose food allergy and should not be used as the basis for recommending an elimination diet.

Unusual Clinical Scenarios to Consider in Patient Management

Allergic contact dermatitis may be a complicating factor in patients with atopic dermatitis. Contact dermatitis may develop to products used therapeutically, including emollients, corticosteroids, other anti-inflammatory agents, as well as to other environmental or occupational allergens. Persistent moderate to severe dermatitis, or dermatitis exacerbations with exposure to potential allergens, should prompt evaluation and patch testing.

What is the Evidence?

Beck, LA, Thaçi, D, Hamilton, JD, Graham, NM. "Dupilumab treatment in adults with moderate-to-severe atopic dermatitis". N Engl J Med. vol. 371. 2014 Jul 10. pp. 130-9.

(A monotherapy study that shows the efficacy of dupilumab, a human monoclonal antibody that blocks IL4 and IL13.)

Thaçi, D, Simpson, EL, Beck, LA, Bieber, T. "Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial". Lancet. vol. 387. 2016 Jan 2. pp. 40-52.

(A randomized, double blind, placebo controlled study investigating the efficacy and safety of various dupilumab treatment regimens.)

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