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Modifying the Course of Atopic Dermatitis

Maha Theresa Dutil, MD, MEd, FRCPC

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Women's College Hospital, Toronto, ON, Canada

Introduction

Atopic dermatitis is a chronic inflammatory skin condition. It has a relapsing course characterized by flare-ups of acute eczema on a background of chronically dry skin. The association of atopic dermatitis (AD) with asthma and allergic rhinitis is referred to as the atopic triad. Conventional strategies have focused on avoidance of triggers and pharmacologic intervention during flares, however, with greater insights into disease etiopathogenesis, prophylaxis of flare-ups with topical immunosuppression and skin barrier protection represent recent changes in AD prevention and management.

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Pathogenesis

  • Atopic dermatitis is the most common pediatric chronic skin disease.
  • AD occurs mainly in infants, with almost half of all cases occurring within the first 6 months of life, but can also be seen in children; AD can last into adult years in approximately 40% of those children.1
  • The prevalence of AD in Canada was estimated to be 8.5% for children aged 6-7 years and 9.4% for children aged 13-14 years. Lifetime prevalence is estimated to be up to 17%, but continues to increase.
  • About 10-15% of cases are severe with the remainder split between mild and moderate.2,3

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Diagnosis

  • The morphology of AD lesions is the same as that of any dermatitis and includes erythema, vesicle and papule formation, exudation, excoriation, crusting, scaling, and sometimes lichenification. Hence, one cannot use morphology alone to make the diagnosis. Instead, it is necessary to consider the constellation of features associated with AD, these include:
    1. Pruritus (the hallmark of AD; do not make the diagnosis without a history of itch)
    2. Early age of onset
    3. Typical morphology and distribution
    4. Personal or family history of atopy (50-70% of patients with AD have a first-degree relative with atopy)
    5. Xerosis
    6. Chronic relapsing course (no cure)
  • The itch, which can be intractable, has important psychological implications. It causes emotional stress and sleep disturbances that significantly impact quality of life. In children, it can impact school performance and, in adults, work performance.
  • AD usually begins at 3 months of age, sometimes earlier, with symmetrical involvement of the cheeks, forehead, scalp, and extensor aspects of the extremities.
    • On the torso it stops in the area covered by the diaper.
    • Dry skin is common but becomes more pronounced during the second year of life. After age 2 the lesions are more often located in the antecubital and popliteal fossae, as well as hands, feet, wrists, ankles, and folds of the neck.
  • Most cases of AD seem to disappear during childhood, but when they last into teenage years, lichenification and dryness are typical. In the adult years, facial and hand involvement are typical.4

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Pathogenesis

  • Pathogenic factors include:
    • Genetic predisposition (filaggrin mutations)5
    • Skin barrier abnormalities
    • Inflammatory immune response
    • Environmental factors
  • Patients with AD have skin barrier function defects that increase skin permeability6 and transepidermal water loss (TEWL), and allow the penetration of allergens through the skin.
    • These allergens induce activation of the immune system, driving dendritic cells to enhance Th2 polarization, which in turn produces inflammation and leads to further deterioration of skin barrier function. This is referred to as the outside-inside-outside theory of AD pathophysiology.
    • The dramatic increase in prevalence of AD since World War II suggests that environment-gene interactions must play an important role in its pathogenesis.
    • Additionally, increased exposure to soaps, bubble-baths, and water further aggravate an already damaged skin barrier.

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General Skin Care

Caring for atopic skin must be as continuous as the disease is chronic. It is important to educate the patient or caregiver about AD and explain that the care cannot stop when the flare is over and that good skin care may reduce acute flares by improving the compromised skin barrier and reducing TEWL.7

  • The mainstay of basic AD management is the regular use of moisturizers together with good skin hydration, and the avoidance of known triggers.
    • The amount of moisturizer used must be generous and the method of application should be demonstrated to the patient/caregiver as they tend to use too small a quantity.
  • Practical tips for AD management:
    • Wash clothes with mild laundry detergent; double-rinse
    • Avoid fabric softener and bleach
    • Dress in cotton and soft fabrics, avoiding wool
    • Keep the humidity in the house around 45-55%
    • Bathe 1-3 times daily in lukewarm water for 5-10 minutes
    • Use emulsifying oil in the bathwater
    • Use mild syndets with adjusted pH for cleansing
    • Pat dry, do not rub, and apply moisturizer immediately after bathing while the skin is still damp

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Treatment of Atopic Dermatitis

The common treatment approach for AD has been a reactive one with the use of moisturizers daily and the application of topical steroids or calcineurin inhibitors reserved for acute flares. An alternative treatment approach has been investigated in clinical trials and is known as proactive therapy, preventative therapy or maintenance therapy. This approach has been labelled a paradigm shift in the treatment of AD.8

Topical Steroids

  • First-line therapy of AD in children consists of using a mild to moderately potent topical steroid combined with the general skin care previously described.
  • To maximize benefit and reduce risk, one must choose a topical steroid strength and vehicle by considering the age of the patient, site of the dermatitis, extent and severity of the disease, morphology of the lesion (which guides in choice of the vehicle), and duration of therapy.
  • Treating only acute flares, however, does not adequately control the disease since there is subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities present in the skin of patients with atopic dermatitis even where no lesion is seen. This provides a rationale for ongoing treatment to control that inflammation rather than wait for an acute flare.
  • The long-term use of topical steroids is limited by potential local and systemic side-effects.
  • Although an important tool in short courses for the treatment of severe AD flares, topical steroids can cause problems if used chronically, especially on the face or in the skin folds, causing atrophy, telangiectasia, and striae.
  • If too potent a steroid is used over a large area, suppression of the hypothalamic pituitary axis can occur.
  • Just as it is important to demonstrate the application of a moisturizer, it is important to demonstrate the application of topical steroids. When used properly side-effects can be avoided and patient education can reduce steroid phobia.
  • There are a few studies looking at the long-term use (16-40 weeks) of topical steroids twice-weekly on unaffected skin to prevent flares of atopic dermatitis.9-11

Topical Calcineurin Inhibitors (TCI)

The TCIs available in Canada, tacrolimus 0.03% and 0.1% ointments and pimecrolimus 1% cream, provide antiinflammatory steroid-free therapy for atopic dermatitis. They act by inhibiting the activity of calcineurin to dephosphorylate the nuclear factor of activated T cell, and thus, suppress T cell cytokine production.

  • They are safe and effective treatment options for children and adults with atopic dermatitis.
  • They are indicated for short-term and long-term intermittent therapy in non-immunocompromised patients aged ≥2 years.
  • They are extremely effective in alleviating the itch of atopic dermatitis, thereby improving the quality of life of the patients and their family members.12
  • Treatment with TCIs (and topical steroids) is associated with reduced colonization with Staphylococcus aureus (S. aureus) on the lesional skin of patients with AD.
  • They can be used on any body surface including face, eyelids, and folds, and are not associated with atrophy. In fact, there is evidence to suggest that tacrolimus can reverse steroid induced atrophy.13
  • The most common side-effect is local discomfort, described by some patients as increased itching, burning or stinging experienced during the first few days of therapy, which usually lasts only 10-15 minutes upon application.
  • Absorption through the skin is low and there is no evidence of systemic toxicity.14

Maintenance Therapy

  • To address the issues of subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities present in the non-lesional skin of AD patients, ongoing twice-weekly treatment with tacrolimus ointment was compared with conventional reactive therapy with tacrolimus ointment.
  • Patients with any severity of AD received stabilization therapy with tacrolimus ointment for up to 6 weeks to control the disease. Once controlled, they were randomized to ongoing twice-weekly treatment with active drug or vehicle for 1 year. The vehicle arm represents the current standard regimen of treating disease flares. AD flares were treated with twice-daily tacrolimus ointment until resolution.15,16
  • Results showed that twice-weekly tacrolimus ointment reduced the number of flares, prolonged the flare-free interval, and was well tolerated without increasing the amount of ointment used. See Table 1.
  • The trial results led to Health Canada's approval of tacrolimus ointment 0.03% and 0.1% for a new indication. It can be prescribed for maintenance therapy to prevent flares and prolong flare-free intervals in patients with atopic dermatitis who experience a high frequency of flares (≥5 times per year).
Prophylactic Adult Reactive Adult Prophylactic child Reactive child
Median time to first flare 142 days 15 days 217 days 36 days
No flares in moderate-severe AD 42.5% 12.3% 41% 14.7%
Daily use in moderate-severe AD ~ 2 g ~ 2 g 1.3 g 1.4 g
Table 1. Comparison of tacrolimus as maintenance or reactive therapy15,16

Adjuvant Therapy

  • Oral antihistamines can provide symptomatic relief of the itch, particularly at bedtime (due to their sedating properties), if topical therapy alone is inadequate.
  • Topical or systemic antibiotics may be necessary to treat impetiginized atopic dermatitis. Both topical steroids and calcineurin inhibitors in the long-term will reduce staphylococcal colonization, but at times reducing colonization with the use of bleach baths and intranasal application of mupirocin ointment may be necessary.
  • Patients with atopic dermatitis can develop wide-spread infection with herpes simplex, referred to as eczema herpeticum or Kaposi's varicelliform eruption. Prompt recognition and treatment with oral acyclovir may prevent complications of this potentially life-threatening infection.

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Conclusion

Atopic dermatitis is a common chronic inflammatory skin condition that can be difficult to treat. The key to successful therapy is education of the patient/caregiver in the principles of general skin care that have been discussed. Advancements in AD pathophysiology have led to improvements in therapy and the option of steroid-free treatment. The understanding of subclinical inflammation, epidermal barrier dysfunction, and immunological abnormalities in what appears to be normal looking skin has led to the use of maintenance or preventative therapy to keep the disease under control and break the cycle of repeated flares.

References

  1. Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr 3;358(14):1483-94.
  2. Barbeau M, Lalonde H. Burden of Atopic dermatitis in Canada. Int J Dermatol. 2006 Jan;45(1):31-6.
  3. Lynde C, Barber K, Claveau J, et al. Canadian practical guide for the treatment and management of atopic dermatitis. J Cutan Med Surg. 2005; 8 (Suppl 5):1-9.
  4. Leung AK, Hon K, Robson W. Atopic dermatitis. Adv Pediatr. 2007;54:241-73.
  5. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011 Oct 6;365(14):1315-27.
  6. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908.
  7. Loden M. The skin barrier and use of moisturizers in atopic dermatitis. Clin Dermatol. 2003 Mar-Apr;21(2):145-57.
  8. Schmitt J, von Kobyletzki L, Svensson A, et al. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011 Feb;164(2):415-28.
  9. Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ. 2003 Jun 21;326(7403):1367.
  10. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 2002 Sep;147(3):528-37.
  11. Van Der Meer JB, Glazenburg EJ, Mulder PG, et al. The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br J Dermatol. 1999 Jun;140(6):1114-21.
  12. Whalley D, Huels J, McKenna SP, et al. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents' quality of life in the treatment of pediatric atopic dermatitis. Pediatrics. 2002 Dec;110(6):1133-6.
  13. Boguniewicz M, Schmid-Grendelmeier P, Leung DY. Atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):40-3.
  14. Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007 Apr;127(4):808-16.
  15. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol. 2008 Dec;159(6):1348-56.
  16. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy. 2008 Jun;63(6):742-50.

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