Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 18th Congress of the European Academy of Dermatology and Venereology

Berlin, Germany / October 7-11, 2009

A key influence on skin barrier integrity is transepidermal water loss (TEWL). To illustrate how different atopic dermatitis therapies can affect TEWL, Dr. Michael J. Cork, University of Sheffield, UK, cited a study conducted to compare topical corticosteroids, tacrolimus and a control agent (Cork MJ. ISAD 2008). Findings indicated that the steroids resulted in 60% loss of corneodesmosome density and substantial TEWL. In contrast, TEWL with the topical calcineurin inhibitor (TCI) tacrolimus was indistinguishable from that of a control substance.

“Topical corticosteroids are extremely effective treatment in short courses for severe flares of atopic dermatitis,” stated Dr. Cork. “We only run into problems when we use them chronically. As our patients have told us for years, if they use them chronically, especially on the face, it may lead to exacerbation of atopic dermatitis, so-called steroid addiction.”

In another study, Dr. Cork and colleagues directly compared a topical corticosteroid (betamethasone valerate) and topical tacrolimus on volunteers. Investigators applied the topical corticosteroid to one arm and tacrolimus to the other for three weeks, during which time they performed tape-stripping evaluations. At the end of the study, the high-potency steroid had resulted in a high rate of TEWL whereas no impact on TEWL was observed with the TCI. “In my practice, the most effective way to treat atopic dermatitis is combination therapy with emollients, a TCI such as tacrolimus, and short courses of high-potency topical corticosteroids, continued for no more than about three weeks at a time,” Dr. Cork told delegates.

Pathophysiology of Atopic Dermatitis

Almost half of all cases of atopic dermatitis have an onset within the first six months of life (Bieber T. N Engl J Med 2008; 358:1483-94). At that early age, atopic dermatitis often is not “atopic,” unrelated to any allergic reaction, noted Prof. Thomas Bieber, University of Bonn, Germany. “In fact, more than half of children affected before 2 years of age have no evidence of IgE sensitization, which usually occurs later in the course of the disease,” he remarked. “Similarly, many people who develop atopic dermatitis in adulthood show no sensitization at first.”

Genetic mutations that lead to skin barrier dysfunction provide the window of opportunity for inflammation. The impaired skin barrier becomes susceptible to penetration by environmental allergens, which drive dendritic cells to enhance Th2 polarization. “There is subclinical inflammation present in the skin of patients with atopic dermatitis even when no visible lesions are present,” observed Prof. Bieber.

The inflammation increases the skin’s susceptibility to infection in patients with atopic dermatitis. Some studies have shown that up to 90% of patients have skin colonization by Staphylococcus aureus (Verhagen et al. J Allergy Clin Immunol 2006;117:176-83). Moreover, production of bacterial endotoxins has been associated with exacerbations of atopic dermatitis (Bieber T. N Engl J Med 2008).

Autoimmunity also plays a role in at least some cases of atopic dermatitis, Prof. Bieber continued. About 25% of adults with atopic dermatitis have IgE antibodies against self-proteins. Serum levels of the autoantibodies correlate with disease severity, and IgE antibodies against autoantigens in the skin can perpetuate allergic inflammation (Bieber T. N Engl J Med 2008).

Rationale for Ongoing Treatment

Evidence of continuous, subclinical inflammation provides a rationale for ongoing active treatment to control the inflammation. The subclinical inflammation inevitably progresses to clinical inflammation and recurrent disease flares, noted Prof. Bieber. By continuously controlling subclinical inflammation, ongoing active management disrupts the cyclical nature of the disease process and prevents flares.

According to Dr. Sakari Reitamo, Helsinki University, Finland, ongoing active treatment of atopic dermatitis has demonstrated superiority over the old therapeutic paradigm based on treatment of flares.

Recently, ongoing twice-weekly treatment with topical tacrolimus was compared with conventional reactive therapy with this TCI (Thaçi et al. Br J Dermatol 2008;159:1348-56, Wollenberg et al. Allergy 2008;63:742-50). Patients with any severity of atopic dermatitis received stabilization therapy with the TCI for as long as six weeks to control flares. They were then randomized to ongoing, twice-weekly treatment with tacrolimus ointment or ointment vehicle. Disease flares were treated until resolution with twice-daily TCI ointment.

“The vehicle arm of the study represented the current standard regimen of reactive flare treatment with tacrolimus,” reported Dr. Reitamo. “Results showed that twice-weekly tacrolimus ointment reduced the number of flares and prolonged the flare-free interval, and was well tolerated.” Regarding prophylactic therapy vs. reactive therapy, median time to first flare was significantly prolonged in adults (142 vs. 15 days) and in children (217 vs. 36 days), both P<0.001.

Investigators performed a post-hoc analysis limited to patients with moderate or severe atopic dermatitis. In both children and adults, the twice-weekly regimen significantly reduced the number of flares compared with reactive therapy (P<0.001).

About three times as many patients in the twice-weekly TCI arm had no disease flares as compared with the control arm, Dr. Reitamo continued. Among adults, 42.5% had no flares with twice-weekly tacrolimus ointment compared with 12.3% of adults treated with reactive therapy (P<0.001). A similar difference emerged from an analysis of data for pediatric patients: 41% flare-free with ongoing TCI therapy vs. 14.7% with reactive therapy (P<0.001).

In children and adults, the two TCI regimens demonstrated similar tolerability. Moreover, the average daily use of TCI ointment was similar in the two treatment arms. The improved disease control with proactive therapy did not increase medication use, noted Dr. Reitamo. Daily use of tacrolimus ointment averaged about 2 g in both adult treatment arms and 1.3 to 1.4 g in the pediatric cohort.

Dr. Reitamo explained the trial results have led to the European Union’s acceptance of ongoing therapy with tacrolimus as the standard of care for children and adults with moderate or severe atopic dermatitis. For adults, the twice-weekly regimen should be reviewed after 12 months to determine whether maintenance therapy should be continued in the absence of safety data for continuing maintenance therapy beyond that time. For children on twice-weekly therapy, the regimen should be stopped after 12 months to decide whether treatment should continue.

No Increased Risk of Malignancy

Introduction of TCIs raised some concern about a theoretical risk of malignancy. That concern has not been borne out in more than 15 years of clinical investigation and use, remarked Prof. Carle Paul, Dermatology Head, Toulouse University, France.

Several epidemiologic studies have confirmed the lack of an increased malignancy hazard in patients treated with TCIs. In one study, investigators compared 1946 patients with atopic dermatitis treated with TCIs and 875 patients who had not received the agents. The results showed no evidence of an increased risk of nonmelanoma skin cancer in users of the TCIs (Margolis DJ, Hoffstad O, Bilker W. Dermatology 2007; 214:289-95).

Similarly, analysis of a database representing almost 300,000 patients with atopic dermatitis showed no association between use of TCIs and an increased risk of lymphoma. In fact, only the severity of atopic dermatitis predicted an increased risk of lymphoma (Arellano et al. J Invest Dermatol 2007; 127:808-16).

“Overall, tacrolimus ointment is a well-tolerated treatment for moderate and severe atopic dermatitis,” Prof. Paul concluded. “Systemic exposure to tacrolimus is very low, and there is no evidence of an increased risk of malignancy in patients using tacrolimus ointment.”