A New Paradigm Shift in the Management of Atopic Dermatitis

Marc Bourcier, MD, FRCPC
Faculty of Medicine, Sherbrooke University, Sherbrook, QC, Canada
Dermatology Clinic, Moncton, NB, Canada

Introduction

Atopic eczema (or atopic dermatitis) is a common inflammatory skin condition that dermatologists, pediatricians, family physicians, and primary-care providers see on a daily basis. It generally presents as a chronically relapsing, highly pruritic, inflammatory skin disease that is associated with significantly reduced quality of life for patients and their families. Irritability, fatigue, sleep disturbances, treatment dependence, mood changes, and other psychological sequelae are frequently reported. Also, the social stigma associated with this visible skin condition should not be neglected.^1-3

Overview of Atopic Dermatitis

• Eczema is characterized by a chronic course of recurring flares, as it often presents with periods of remission and flare-ups; continuous treatment and skin care are necessary.^1-3
• Eczema can occur at any age, but it typically appears in early childhood (although late-onset disease is possible), with disease flares occurring periodically throughout the patient's life.¹
• It is estimated that up to 17% of Canadians will develop atopic eczema at some point during their lifetime.⁴
• Atopic eczema has become more prevalent over the past few decades. Approximately half of eczema patients will develop the disease before 1 year of age.² Of these, approximately one-third will continue to suffer from eczema in adulthood.
• Most patients (approximately 85%) have mild to moderate disease.¹

Pathogenic and Other Contributing Factors

• The exact cause of atopic eczema is unknown, however, it is believed to have a multifactorial pathogenesis, with genetics, impaired immune responses, the environment, and skin barrier defects being the most predominant contributing factors.³
• The epidermis is the body's first line of defense against environmental insults, as it forms a protective layer between the body and exogenous factors.⁵
• An intact epidermal layer is essential for the skin to function as a physical and chemical barrier against environmental agents.⁵
• Any breakdown in the epidermis increases skin moisture loss and the penetration of infectious and noxious external agents.⁵
• Several genetic factors are known to contribute to the dysfunction of the epidermal barrier in atopic eczema.
• In particular, genetic defects associated with increased IgE (antibody) production and protease expression, and decreased levels of structural proteins in the epidermis have been linked to atopic eczema.
• Gene mutations are believed to engender some of the aforementioned structural abnormalities in the epidermis and induce immune dysregulation.⁴
• The scratching that can result from symptomatic pruritus may additionally cause skin trauma and excoriation, potentially leading to further inflammation, disease exacerbation, and secondary infections.
• Environmental factors may also contribute to skin barrier dysfunction, including washing with harsh soaps and detergents, and exposure to various infectious and noxious agents.
• Soap or detergent use is one of the most common triggers of atopic eczema flares by adversely affecting the skin barrier. The use of inappropriate cleansing agents increases transepidermal water loss (TEWL), induces the release of pro-inflammatory cytokines, and elevates skin pH - provoking scaling, dryness, tightness and roughness, erythema, and swelling.

Top    

Treatment Rationale

Management of atopic dermatitis is frequently multimodal, incorporating several non-pharmacologic and pharmacologic approaches.

• Basic skin care practices, such as quick daily bathing and gentle cleansing of skin with mild, unscented soaps/ cleansers, followed by moisturization (hydration) with emollients can minimize the skin impairment and treat the symptoms of dry skin and itching.⁶
• Additionally, the avoidance of irritants and other triggers known to exacerbate atopic eczema may prove useful in preventing flares.⁶
• However, despite vigilant skin care practices, most patients will continue to experience atopic eczema symptoms and recurrent flares that will require pharmacologic treatment.⁶

Top    

Treatment Options

Topical Corticosteroids

• Topical corticosteroids have been the predominant atopic eczema therapy for more than four decades - they provide flare control through their anti-inflammatory, antiproliferative, immunosuppressive, and vasoconstrictive actions.
• Common adverse effects of topical corticosteriods include striation, skin thinning and atrophy, and potential systemic effects.³

Topical Calcineurin Inhibitors

• The topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, are alternative topical anti-inflammatory agents in the clinician's armamentarium.
• These agents may be used on all body parts, including sensitive areas, such as the face, neck, and groin.
• They can also be used in patients who have experienced steroid related side-effects or in those suffering from a chronic disease that is unresponsive to topical steroids, as well as in patients for whom therapy with steroids is inadvisable or has been unsuccessful.²
• The calcineurin inhibitors do not cause the adverse effects on collagen synthesis or skin thickness as compared with topical corticosteroids.⁷
• Long-term treatment with tacrolimus has also been associated with improvements in collagen synthesis and skin thickness.⁷

Antimicrobials

• Antimicrobials are commonly prescribed for clinically infected eczematous lesions where Staphylococcus aureus colonization is suspected as a contributing factor.
• Short-term combination topical therapy with an antibiotic and corticosteroid is widely used. However, overuse and prolonged treatment increases the risk for developing antibiotic resistance.
• A recent report in Cochrane Database Systematic Review did not find clear evidence of benefit for antimicrobial interventions in atopic dermatitis patients.⁸

Lifestyle/Non-pharmacologic Strategies

• Identify and eliminate triggering factors
• Avoid allergens
• Environmental (e.g., house dust, dust mites, pollens, animal dander, moulds, smoke)
• Food (e.g., milk, egg whites, peanuts, soybeans, tree nuts, fish, shellfish, wheat)
• Minimize exposure to irritants (e.g., wool, perfumes, soap, hot baths or showers)
• Use emollients to hydrate and rehydrate
• Ensure that sports equipment is dried completely - sweat is a common irritant
• Encourage patient self-education, suggest visiting reputable websites (e.g., Canadian Skin Patient Alliance, Eczema Society of Canada, and the Canadian Dermatology Association)

A Paradigm Shift in the Management of Eczema

• Conventional therapeutic approaches have been recently challenged by a newer strategy that takes a preventative long-term approach to treating atopic eczema.^7,9
• The clinical justification for preventative maintenance therapy is that it can improve atopic eczema related skin barrier dysfunction and diminish the immunological inflammatory abnormalities often associated with chronic eczematous flares and disease exacerbation.⁹
• The preventative maintenance approach uses intensive topical anti-inflammatory therapy until visible lesions have nearly cleared.^7,9 This is followed by low dose intermittent application, usually twice weekly, of anti-inflammatory agents to previously affected skin areas to prevent flares and disease exacerbation.^7,9
• Several clinical trials comparing the preventative to the traditional "reactive" approach using topical corticosteroids have shown that preventative therapy is an effective strategy.¹⁰
• In 2002, Hanifin et al. published a randomized, doubleblinded, 20-week clinical trial comparing the preventative application of 0.05% fluticasone cream with vehicle cream.¹¹
• Patients preventatively receiving 0.05% fluticasone cream were 7.7 times less likely to experience a flare relapse than those receiving vehicle.
• Alternatively, preventative use of 0.1 % and 0.03% tacrolimus ointment was recently studied in two large, multicentre, randomized, double-blind, 12-month clinical trials involving adult (n=257) and pediatric (n=125) atopic eczema patients.⁹
• Patients were randomized to twice-weekly preventative tacrolimus therapy or twice-weekly vehicle after an initial flare treatment with twice-daily tacrolimus ointment.
• Preventative application of tacrolimus significantly reduced the number of disease exacerbations requiring substantial therapeutic intervention in both treatment populations.
• Preventative therapy also resulted in significantly fewer treatment days (12.4 vs. 31.5), and increased flare-free time until first relapse (142 days vs. 15 days) in adult patients.^9-14 In addition, preventative therapy in children significantly reduced the number of treatment days (34.0 vs. 59.9), and prolonged the time to first relapse compared with reactive treatment (295 days vs. 56 days).^12-15
• Similar results have also been shown in trials reporting the use of pimecrolimus cream for flare prevention in children.¹³
• TCIs may offer benefits over corticosteroids in the long-term treatment of atopic eczema given their lack of association with skin atrophy and decrease in collagen synthesis.^3-7,9
• Based on the above studies, in September 2010, Health Canada approved a new indication for the use of tacrolimus ointment as maintenance therapy in moderate to severe atopic dermatitis.¹⁶

Top    

Conclusion

As there is no cure for atopic eczema, a long-term strategy for disease control and management is of significant importance for this chronically relapsing condition. Recent insights into the mechanisms that drive cutaneous inflammation have led to a better understanding of atopic eczema and highlighted the role of the epidermal barrier in its pathogenesis. Targeting the skin barrier and restoring its function may prove an effective treatment strategy for atopic eczema. Preventative treatment with topical steroids and TCIs offer a novel therapeutic approach with clinical implications for physicians and their patients. Furthermore, studies have shown that topical tacrolimus may confer additional benefits, as it improves the functionality of the skin barrier and does not cause skin atrophy. As demonstrated in clinical investigations, the substantial reduction in flare-ups among preventatively treated patients may result in fewer atopic eczema-related physician visits and quality of life improvements (e.g., work/school performance).

References

1. Bieber T. Atopic dermatitis. N Engl J Med 358(14):1483-94 (2008 Apr 3).
2. Lynde C, Barber K, Claveau J, et al. Canadian Practical Guide for the Treatment and Management of Atopic Dermatitis. J Cutan Med Surg (Epub: 2005 Jun 30).
3. Ong PY, Boguniewicz M. Atopic dermatitis. Prim Care 35(1):105-17 (2008 Mar).
4. Barnes KC. An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy Clin Immunol 125(1):16-29 e1-11 (2010 Jan).
5. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129(8):1892-908 (2009 Aug).
6. 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 24(3):317-28 (2010 Mar).
7. Rustin MH. The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br J Dermatol 157(5):861-73 (2007 Nov).
8. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, et al. Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Cochrane Database Syst Rev (3):CD003871 (2008).
9. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 63(6):742-50 (2008 Jun).
10. Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis--an emerging concept. Allergy 64(2):276-8 (2009 Feb).
11. 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 147(3):528-37 (2002 Sep).
12. 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 159(6):1348-56 (2008 Dec).
13. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol 22(11):1290-301 (2008 Nov).
14. Wollenberg A, Sidhu MK, Odeyemi I, et al. Economic evaluation of maintenance treatment with tacrolimus 0.1% ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 159(6):1322-30 (2008 Dec).
15. Thaci D, Chambers C, Sidhu M, et al. Twice-weekly treatment with tacrolimus 0.03% ointment in children with atopic dermatitis: clinical efficacy and economic impact over 12 months. J Eur Acad Dermatol Venereol 24(9):1040-6 (2010 Sep).
16. Tacrolimus ointment (Protopic®) product monograph. Astellas Pharma Canada, Inc., Markham, ON, Canada (2010 Sep).

Top    

• A New Paradigm Shift in the Management of Atopic Dermatitis
• Topical Approaches in Combination Therapy for Acne