Atopic Dermatitis


Key Points

  • Atopic dermatitis is a chronic, intermittent disease. It is most prevalent in children but affects all ages.
  • Atopic dermatitis is commonly found in association with allergic rhinitis, asthma, or other manifestations of atopy.
  • There are three likely related pathophysiologic mechanisms underlying the disease: skin inflammation (T helper cell dysregulation), an epidermal barrier defect (ceramide, filaggrin) and genetics.
  • Treatment involves an initial therapy to reduce inflammation as well as a long-term maintenance regimen. Skin care is critical to the initial treatment and to the maintenance plan.

Introduction

Epidemiology

Atopic dermatitis can affect all age groups, from newborns to adults, but is far more prevalent among children. The prevalence of atopic dermatitis in developed countries is estimated to be 15–20% in children and 2–10% in adults. Approximately 70% of patients with atopic dermatitis have a family history of atopy (atopic dermatitis, allergic rhinitis, or asthma).

Pathophysiology

Two hypotheses have been proposed for the pathogenesis of atopic dermatitis:

  • Immunological: The primary defect is an immunological disturbance that causes IgE-mediated sensitization, with epidermal-barrier dysfunction regarded as a consequence of the local inflammation.
  • Defective skin barrier: This hypothesis proposes that an intrinsic defect in the epithelial cells leads to barrier dysfunction; the immunological aspects are considered to be secondary.

Clinical Presentation

In newborns or infants, the first eczematous lesions usually present on the cheeks and scalp and on the extensor surface of the knees and elbows. Scratching, which frequently starts a few weeks later, causes crusted erosions. During childhood, lesions involve flexures (knee and elbow), the nape, and the dorsal aspect of the limbs. In adolescence and adulthood, lichenified plaques affect the flexures, head, neck and hands.

Initial Evaluation

The diagnosis of atopic dermatitis is largely based on the clinical presentation. The United Kingdom Working Party’s diagnostic criteria for atopic dermatitis proposed patients must have pruritic skin plus 3 or more of the following: history of flexural involvement, a history of asthma/hay fever, a history of a generalized dry skin, onset of rash under the age of 2 years, or visible flexural dermatitis.

Skin biopsy and laboratory testing are not routinely necessary to establish a diagnosis of atopic dermatitis. Skin biopsies performed, however, to exclude other skin disease. Bacterial or viral culture can be performed if secondary infection is suspected.

Erythematous, scaly, excoriated symmetric plaques on the face, with sparing of the nasal tip. Face and neck involvement is common.

Other body areas can be affected with more erythema or more dull, less erythematous eczematous plaques.


Excoriated, fissured, lichenified erythematous plaques of atopic dermatitis in a bilateral, symmetric distribution affecting the popliteal fossa, a commonly affected site.

Lichenification may result in loss of the lateral aspect of the eyebrows, also known as Hertoghe’’s sign.

Hypopigmented patches with subtle scale, also known as pityriasis alba, occur regularly in atopic dermatitis.

Fissuring is common in the retroauricular fold. Bacterial superinfection (seen as crusting) within fissures is a common complication.

Keratosis pilaris or follicular hyperkeratosis is also found in atopic dermatitis.

Hyperlinearity of the palms is often seen.


Erythematous scaly, excoriated plaques with fissures and honey-colored crusting may be especially evident on the glabella, on the upper cutaneous lip, and in the periocular area. This is highly suggestive of impetiginized (superinfected) facial eczema.


Differential Diagnosis

Allergic contact dermatitisContact dermatitis can closely resemble and coexist with atopic dermatitis. Clues to contact dermatitis can include exposure history as well as unusual localization or geometric morphology to eruption. Patch testing can be helpful in confirming an allergic contact dermatitis.

Scabies: Scabies can closely mimic the appearance of atopic dermatitis. Involvement of the skin folds (including web spaces, mammary areas, and genitalia) and the presence of burrows can suggest a diagnosis of scabies. Exposure to a crowded or institutional setting (hospitals, nursing homes, prisons) is also a risk factor. Mites or eggs may be demonstrated on skin scraping of biopsy.

Psoriasis: In contrast to atopic dermatitis, psoriasis typically involves the extensor surfaces of the skin and is more well-demarcated.

Treatment

General Principles of Management

Effective management of atopic dermatitis must address 4 major issues:

  1. Skin Barrier: Repair of the barrier through hydration and consistent use of emollients.
  1. Inflammation: Use of an anti-inflammatory agent, either topical or systemic; in most cases, this can be a topical corticosteroid.
  1. Pruritus: Is a subjective symptom and also an exacerbating factor in atopic dermatitis that can result in significant morbidity (i.e., lack of sleep, excoriations that further impair the skin barrier and predispose to secondary infection).
  1. Superinfection / Colonization: Secondary infection, commonly by Staphylococcus aureus (impetiginization) and sometimes by herpes simplex virus (eczema herpeticum) often exacerbates inflammation. Reducing secondary skin colonization by staph bacteria may result in significantly reduced skin inflammation.

Therapy should be based on the extent of skin involvement (i.e., generalized vs. localized disease).

  • Localized / mild disease: Usually managed by topical corticosteroids and liberal use of emollients, reduction of bacterial colonization, and reduction of pruritus.
  • Generalized / moderate-to-severe disease: May require use of topical corticosteroids and emollients, UV phototherapy, systemic immunosuppression, or biological agents; reduction of bacterial colonization and pruritus management is essential.

Mild-to Moderate Disease

  1. Skin Barrier
  1. Suppression of Inflammation: Corticosteroids.
    • Topical corticosteroids are the mainstay of therapy for atopic dermatitis and are typically applied twice daily. The formulation (ointment, cream, lotion) should offer the most emollient benefit. The potency of the corticosteroid should be matched to the severity of disease and to the site. Topical calcineurin inhibitors may be an alternative to topical corticosteroid use, especially at sites prone to atrophy (face, neck, and intertriginous areas).

Low potency steroid:

  • Hydrocortisone 1% or 2.5% lotion, cream, or ointment.

Low-medium potency steroid:

  • Hydrocortisone butyrate 0.1% (such as Locoid) ointment, cream, or lotion.
  • Desonide 0.05% (such as Desonate, Desowen, LoKara, Verdeso) lotion, cream, ointment, or foam.
  • Mometasone furoate 0.1% (such as Elocon) lotion, cream, or ointment.

Medium potency steroid:

  • Triamcinolone acetonide 0.1% lotion, cream, or ointment.

Potent steroid:

  • Fluocinonide 0.05% or 0.1% (such as Lidex or Vanos) lotion, cream, or ointment.

Superpotent steroid:

  • Clobetasol propionate 0.05% (such as Clobex, Embeline, Olux, Temovate) foam, gel, lotion, cream, or ointment.
  • Betamethasone dipropionate 0.05% (such as Diprolene).
Site Best Vehicle Mild Disease Moderate Severity Severe Disease Frequency
Face, axillae, groin Cream Hydrocortisone 1% or 2.5% Desonide 0.05% Mometasone 0.1% (up to 5-7 days) Daily to twice daily
Scalp Lotion or foam Desonide 0.05% or Triamcinolone 0.1% Fluocinonide 0.05% Clobetasol 0.05% Daily to twice daily
Trunk, extremities Cream or ointment Desonide 0.05% or Triamcinolone 0.1% Triamcinolone 0.1% Mometasone 0.1% Fluocinonide 0.05% Mometasone 0.1% Fluocinonide 0.05% Clobetasol 0.05% Twice daily
Palms, soles Ointment Desonide 0.05% or Triamcinolone 0.1% Triamcinolone 0.1% Mometasone 0.1% Fluocinonide 0.05% Mometasone 0.1% Fluocinonide 0.05% Clobetasol 0.05% Twice daily

Calcineurin Inhibitors

  • Topical calcineurin inhibitors (Protopic, Elidel) are second-line treatment in atopic dermatitis. They are generally regarded as being as efficacious as a low- to mid-potency topical corticosteroid.
  • Both tacrolimus 0.03% and pimecrolimus have been approved by the FDA for use in patients 2 years and older.
  • Unlike topical corticosteroids, they do not cause skin atrophy or other adverse events (such as glaucoma and cataracts) and may be an alternative to topical steroids for the treatment of eczema on the face, eyelids, neck and intertriginous areas.
  • Adverse effects include transient burning and erythema. In 2006, the FDA placed a boxed warning for risk of lymphoma; however, a subsequent meta‐analysis did not find a statistically significant association between the use of topical calcineurin inhibitors and an increased risk of lymphoma.

Crisaborole

Crisaborole is an anti-inflammatory inhibitor of phosphodiesterase 4 (PDE4) that was approved by the FDA in 2016 for the topical treatment of mild-to-moderate atopic dermatitis in patients 2 years and older.

  1. Suppression of pruritus:
    • All effective antipruritic agents can result in drowsiness as a side effect.
    • Start by prescribing an evening dose, taken approximately 1 hour prior to bedtime. Give oral antihistamines (hydroxyzine, such as Atarax or Vistaril, initially 10 mg at bedtime to 4 times daily increasing to 50 mg up to 4 times daily until pruritus is suppressed, or until specific side effects limit dosage).
    • Diphenhydramine (such as Benadryl) 25–100 mg may be substituted for hydroxyzine as its sedating effect is smaller.
    • Doxepin (such as Sinequan), initially 10 mg at bedtime up to 50 mg at bedtime, may be a good alternative to hydroxyzine or diphenhydramine but its use may be limited by sedation.
    • Less sedating antihistamines like loratadine (such as Claritin) and cetirizine hydrochloride (such as Zyrtec) can be also used.
  1. Treatment of secondary infection:
    • Superinfection with aureus is common, and may present with increased erythema, honey-crusting or serous weeping, but sometimes has minimal apparent symptoms.
    • It is imperative to take bacterial swab cultures to identify the causative agent and determine its antibiotic sensitivities.
    • Patients with obvious bacterial superinfection can be treated with topical mupirocin twice daily for 1-2 weeks.
    • For more extensive infection, cephalexin (such as Keflex) 500 mg–750 mg 3 to 4 times daily or a semisynthetic penicillin (e.g., dicloxacillin 1 g/day for 7–10 days), or tetracycline base antibiotic (doxycycline 100 mg twice daily for 7-10 days).
    • Periodic bleach baths (prepared with 1/4 cup of household bleach in a full bathtub of lukewarm water) several times a week (soaking 20 minutes with brief lukewarm rinse afterwards) may also be an important step towards reducing/preventing bacterial colonization (See handout Skin Care in Atopic Dermatitis).

Subsequent therapy (after rash abates, usually in 7-10 days)

  1. Skin hydration
    • Use emollients daily between flares.
  1. Suppression of inflammation:
    • While it is essential to use a topical steroid appropriate in strength to the severity of the disease, it is also imperative to reduce the potency of steroids as the skin heals in order to avoid potential adverse effects of long-term topical corticosteroid use (skin atrophy, erythema, striae, or telangiectasias).
    • This requires either frequent clinical evaluation to adjust the treatment regimen or patient education on the potencies of their prescribed medications and how to increase or reduce the potency based on the skin inflammation they are observing.
    • Continue soak and smear bathing as possible, now eliminating wet wraps or occlusion.
    • It is important to note that occlusion of topical steroids potentially increases the risk of developing adverse effects.
  1. Suppression of pruritus:
    • Continue antihistamines at maximum tolerated dosage as needed.
  1. Continue gentle skin care as above.

Moderate-to-Severe Disease

Phototherapy

  • Narrowband UVB (311–313 nm) 2–3 times a week, gradually increasing exposure times;
  • Use of UVA light, with or without photosensitizing chemotherapy (topical or systemic psoralen), is an alternative.

Systemic immunosuppression

  • Prednisone (0.5–1 mg/kg/day by mouth given each morning) is first-line immunosuppression and is an effective therapy for acute flares while an intensive topical regimen is implemented.
  • Gradual tapering of the dose is recommended; frequent or long-term use of prednisone is not advisable due to the risk of adverse effects (osteopenia, cataracts, insulin resistance).
  • Cyclosporine (3–5 mg/kg in doses) is a short-term treatment option for patients with moderate to severe disease who do not respond to conventional topical treatments or phototherapy. Once improvement is achieved, the dose should be reduced to the minimal amount necessary to achieve a sustained response.
  • Other systemic immunosuppression alternatives are mycophenolate mofetil (such as Cellcept), azathioprine (such as Imuran), or interferon-gamma (such as Actimmune).

Dupilumab

  • Dupilumab is aninterleukin 4 (IL4) receptor alpha antagonist that down-regulates type 2 immunity. In March 2017, the US FDA approved dupilumab for the treatment of moderate to severe atopic dermatitis (AD) in adults not adequately controlled by topical medications.
  • The efficacy of dupilumab was evaluated in 2 phase-III trials (SOLO1 and SOLO2) that demonstrated a greater reduction in skin disease as assessed by investigator general assessment (clear or almost clear) when compared to placebo (approximately 40 vs. 10 %). Eczema Area and Severity Index (EASI)-75 was achieved by 44–52 % of patients receiving dupilumab compared to 12–15% of those receiving placebo.
  • Injection site reactions and conjunctivitis were more commonly reported in patients receiving dupilumab than placebo. One patient died of an asthma exacerbation after discontinuing dupilumab and caution should therefore be taken before discontinuing dupilumab in patients with asthma.

Skin Care

  • Gentle skin care is paramount (see handout Skin Care in Atopic Dermatitis).
  • Use mild fragrance-free and/or soapless liquid cleansers; soap should be applied only to intertriginous sites (groin and axillae); bathe (briefly) in lukewarm water or as cool water as tolerable; avoid bathing more often than once a day, especially during winter months; avoid wool and acrylic clothing (which can exacerbate itch).
  • It is essential to apply a cream- or ointment-based emollient within several minutes of bathing in order to maximize trapping of moisture on the skin.
  • Note that topical medications should be applied first to the affected areas of skin, with emollient applied afterwards to the non-affected areas of skin.
  • Finally, gentle skin care is an essential mainstay of the maintenance regimen to prevent flares. 

General Measures

  • Education programs for the parental management of AD in children, and self-management in adolescents, improve disease control and should be integrated into the daily routine.
  • Patient education on the role of skin care should be provided using the simplest explanations possible. This will allow integration of proper skin care practices into the daily routine.
  • Identification and avoidance of trigger factors is part of the education to prevent flares from occurring.
  • It is widely accepted that stress can induce and exacerbate atopic dermatitis. Stress-reduction is a possible adjunctive treatment for patients.

Pearls

  • The simplest treatment regimen is highly recommended, as the prescription of multiple medications can result in confusion about the strength, frequency, or site of application.
  • Explicit instructions on the prescription label itself (including site of application) or use of a treatment plan handout may be helpful to avoid under- or over-treatment of skin disease.
  • Daily “soak and smear” bathing. Instruct the patient to soak for 20 minutes daily in tepid to lukewarm water. Three minutes after the bath, with or without having dried the skin with a soft towel, apply steroid ointment to the affected areas with occlusion under plastic kitchen wrap (for localized areas).
  • Other alternatives to occlusion in generalized disease are: a sauna suit or wet wraps (2 layers of pajamas: the inner layer is moistened with water, and the outer layer is dry). See handout, Treatment Plan for Atopic Dermatitis.

Emerging Therapies

Fezakinumab, a human monoclonal antibody against IL-22, showed encouraging results in the treatment of severe atopic dermatitis (AD) in a randomized double-blind trial published in May 2018. Fezakinumab was given intravenously every 2 weeks for 10 weeks, with a mean reduction in SCORAD (scoring AD) at 12 weeks of 13.8 vs. 8 in the placebo group (this was not statistically significant at p= 0.134). However, a significant result was seen in the subgroup with severe AD (baseline SCORAD ≥ 50), where the decline was 21.6 vs. 9.6 (p= 0.029) at 12 weeks and 27.4 vs. 11.5 at 20 weeks (p= 0.01). Moreover, a significant decrease in involved body surface area of 12.4% in the treated group vs. 6.2% in the placebo group was observed (p= 0.009), as well as in IGA (Investigator’s Global Assessment) score (0.7 vs. 0.3, p= 0.034). The aforementioned scores demonstrate continued improvement throughout the duration of the study. The most reported adverse events were upper respiratory tract infections.

Prognosis

Atopic dermatitis is a chronic condition with a relapsing course. The majority of patients (especially those with mild disease) clear by late childhood. However, a subset of patients have persistent disease­—especially those with more severe and long-lasting disease.

Pitfalls

Patients with atopic dermatitis are predisposed to secondary bacterial and viral infections.

Warning Signs and When to Refer

Primary physicians should consider referral to a dermatologist in cases where topical therapies are insufficient to control disease.

Clinical Cases

Case 1

Initial Presentation

  • 9-year-old girl with chronic dry skin, who developed hypopigmented, fine-scaled patches on the face and trunk
  • She reports new pruritus of the skin
  • No prior treatment

Diagnosis

Mild disease

Treatment

  • Counseling on daily skin care (cleansing: soap-free cleanser over the body, mild soap only in the axilla, groin, hands, feet; moisturizing: emollients used immediately after bathing)
  • Face: hydrocortisone 2.5% ointment twice daily
  • Body: desonide 0.05% ointment twice daily
  • Hydroxyzine at bedtime, as needed for pruritus
  • Follow-up in 4 weeks

Follow-up

  • She returns to the clinic with much improved comfort of the skin. There is less scale and her skin appears well-moisturized, but the hypopigmentation persists
  • Recommend hydrocortisone 1% ointment twice daily (face) and hydrocortisone 2.5% ointment twice daily (body)
  • Continue dry skin care, emphasizing that a maintenance regimen is critical to prevent future flares
  • She is reassured that the skin pigmentation will be restored with time and ongoing maintenance therapy

Case 2


Initial Presentation

  • 42-year-old man with eczema since childhood, now generalized despite topical corticosteroid use
  • He presents with extensive skin disease, much of which is lichenified plaques with thick scale; he reports severe pruritus and difficulty sleeping
  • A bacterial culture sent several weeks ago did not reveal bacterial superinfection

Diagnosis

Moderate disease

Treatment

  • Continue topical corticosteroid use now with escalated potency of his medications:
  • Face: mometasone ointment daily
  • Body: clobetasol ointment twice daily
  • Soak and smear with plastic wrap or sauna suit occlusion at night
  • Hydroxyzine at bedtime
  • Follow-up in 2 weeks

Follow-up

  • The patient is improved, now less erythematous but still with lichenified pruritic plaques
  • Recommend continuing topical regimen with addition of NB-UVB 3 times a week
  • Follow-up in 1 month to determine whether phototherapy must be continued and to decide about systemic immunosuppression (such as prednisone or cyclosporine) if the disease is worsening

Case 3


Initial Presentation

  • 4-year-old child with longstanding atopic dermatitis of the face, trunk, arms, and legs, now presenting with acute onset of increased erythema, honey-colored crusting of eczematous plaques, and excoriations of the skin
  • He was previously well managed with hydrocortisone 1% cream and emollient, used once daily
  • One day of low-grade fevers, and he is not sleeping well due to severe pruritus and itching

Diagnosis

Severe disease with superinfection

Treatment

  • Bacterial culture sent to microbiology lab
  • Face: desonide ointment 0.05% twice daily
  • Body: triamcinolone ointment 0.1% twice daily with wet-wrap occlusion
  • Bleach baths (1/4 cup bleach in full bathtub of water, with rinsing afterwards), nightly
  • Cephalexin 3 times daily for 2 weeks
  • Hydroxyzine at bedtime
  • Follow up in 2 weeks

Follow-up

  • A bacterial culture reveals methicillin-sensitive S. aureus
  • The patient’’s skin is much improved
  • Recommendations:
    • Face: hydrocortisone 1% ointment twice daily
    • Body: hydrocortisone 2.5% ointment twice daily
    • Bleach baths 3 times a week
    • Hydroxyzine at bedtime, as needed

References

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Bieber T. Atopic dermatitis. N Engl J Med 2008; 358(14): 1483-1494.

Bissonnette R, Chen G, Bolduc C, et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2A, randomized, placebo-controlled clinical trial. Arch Dermatol 2010; 146(4): 446-449.

Darsow U, Wollenberg A, Simon D et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol 2010; 24(3): 317-328.

Guttman-Yassky E, Brunner PM, Neumann AU, et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial. J Am Acad Dermatol 2018; 78(5): 872-881.e6.

Legendre L, Barnetche T, Mazereeuw‐Hautier J, et al. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systematic review and meta‐analysis. J Am Acad Dermatol 2015; 72(6): 992–1002.

Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 2016; 75(3): 494-503.

Thaçi D, Simpson EL, Beck LA, et al. 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 2016; 387(10013): 40-52.

Williams HC, Grindlay DJ. What’s new in atopic eczema? An analysis of systematic reviews published in 2007 and 2008. Part 1. Definitions, causes and consequences of eczema. Clin Exp Dermatol 2010; 35(1): 12-15.