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PRIORITY PRESS - 10th Congress of the European Society of Contact Dermatitis

Strasbourg, France / September 15-18, 2010

In chronic hand eczema (CHE), symptomatic blisters, itching and painful fissures can severely limit a patient’s capacity to work, leading to diminished quality of life sometimes accompanied by severe psychologic and social problems. “Although CHE is one of the most common diseases seen by dermatologists, it still requires correct diagnosis and classification to ensure appropriate treatment,” Dr. Robin Graham-Brown, University Hospitals of Leicester, UK, told delegates. “Current pharmacologic treatments generally consist of escalating steps beginning with topical corticosteroids, which are fast-acting and effective in the short term. Thereafter, oral corticosteroids may be useful for immediate treatment of an acute flare.” According to the EDEN (European Dermato-Epidemiology Network) hand eczema survey, there is a lack of trials to guide treatment (Br J Dermatol 151(2):446-51). While topical steroids are an established intervention, recurrent or prolonged use can lead to skin atrophy, leading to a weakening of the skin barrier function. Of the few options remaining, there is limited evidence of efficacy and these are often associated with significant toxicities.

BACH Retreatment Data

Given the limitations of treatments and lack of consensus, Dr. Graham-Brown remarked that until now, there has been a clear unmet need for effective long-term management of severe CHE unresponsive to potent topical corticosteroids. The new oral 9-cis-retinoic acid alitretinoin has shown evidence of long-term efficacy with good tolerability in patients with severe, refractory CHE. This has been reported across a number of clinical trials, most notably the BACH (Benefits of Alitretinoin in Chronic Hand Eczema) study, the largest randomized clinical trial in this population to date.

In BACH, 1032 patients with severe CHE unresponsive to topical corticosteroids were randomized to alitretinoin 10 mg/day, 30 mg/day or placebo for up to 24 weeks to determine the percentage of patients achieving “clear” or “almost clear” hands on the Physician Global Assessment (PGA) scale. The majority of patients had hyperkeratotic CHE, but most of those with hyperkeratosis also had signs of inflammation. At 24 weeks, a 75% reduction in signs and symptoms of CHE was reported, with 47.7% achieving “clear” or “almost clear” skin within 12 to 24 weeks. In all forms of CHE, alitretinoin was efficacious, with the greatest response in hyperkeratotic cases.

Investigators at Bocage Hospital, Dijon, and Henri Mondor Hospital, Créteil, France, reported data from extension studies in 2 subgroups of patients in BACH. In the first, 35% whose hands cleared initially but who relapsed within 6 months cleared again in 79.6% of cases, compared to 8.3% for placebo (P<0.001), within 24 weeks of retreatment. They concluded that patients who respond to treatment and later relapse can benefit from a second course, and such retreatment is well tolerated, suggesting that intermittent alitretinoin therapy is suitable for long-term management of CHE.

In the second group of 243 patients who did not respond or had incomplete response to either the 10 or 30 mg/day dose in the initial phase of BACH and had mild or moderate CHE at the end of the study, approximately half responded to retreatment with alitretinoin 30 mg/day. Investigators suggested that either a higher dose or longer treatment cycle might be practical and beneficial to patients who fail initial treatment.

TOCCATA: Real-life Experience

Following alitretinoin approval and completion of the BACH trial, German investigators initiated the non-interventional observational TOCCATA study to assess efficacy and safety of the 9-cis-retinoic acid under real-life daily dermatologic practice conditions in severe CHE patients refractory to potent corticosteroids. It also examined the similarities and differences between that real-life experience and the randomized, controlled clinical BACH trial.

Prof. Thomas Diepgen, Centre for Occupational and Environmental Dermatology, University Hospital, Heidelberg, Germany, told delegates, “Despite fundamental differences in methodology, both studies investigated the use of alitretinoin in CHE patients.”

While TOCCATA was a non-interventional study, “enrolment reflected the labelled indication of adults with severe CHE refractory to potent topical corticosteroids and, in accordance with the product, special warnings and precautions for female patients of child-bearing age. Pregnancy is an absolute contraindication to alitretinoin treatment because, like all vitamin A acid derivatives, it is teratogenic,” Prof. Diepgen noted. Notwithstanding initial differences in patient selection and enrolment between the trials, he characterized the 2 groups as remarkably similar and highly comparable. A wide range of PGA scores distinguished the groups; in TOCCATA, approximately two-thirds of patients were rated with severe disease and one-third with moderate.

“Treating physicians enrolled 680 patients in TOCCATA based on information in the Summary of Product Characteristics of alitretinoin and a medical evaluation of the patient,” he stated. “Twenty-four weeks of treatment was scheduled, with efficacy and safety parameters documented every 4 weeks. Treatment with alitretinoin 10 or 30 mg/day was carried out at the discretion of the treating physician, with an average duration of treatment exposure of 5 months.”

TOCCATA results showed to be in full alignment with results from BACH, including the safety profile, Prof. Diepgen reported. Regarding the overall primary outcome of “clear/almost clear,” 55.6% of all patients achieved that goal compared to 47.7% of patients in BACH. Outcomes according to baseline morphology tended to be somewhat superior among TOCCATA patients, but the overall trend was the same: severe hyperkeratotic rhagadiform hand eczema patients achieved “clear/almost clear” results in 55.6% compared to 48.7% in BACH, while the figures for severe dyshidrosiform were 44.7% and 33.4%, respectively. Results for severe fingertip eczema were 50.8% and 44.4%, respectively.

Headache and flushing were also less frequently reported in the TOCCATA population: 7.5% vs. 20% and 1.2% vs. 4% for TOCCATA and BACH cohorts, respectively. Dizziness was observed in <1% of both groups. Nearly 80% of patients and physicians rated the efficacy of alitretinoin as “good” or “very good” at treatment end, and fewer than 5% discontinued treatment after the first month.

“I think the take-home message is that alitretinoin works very well and the data from clinical practice are at least as good as those from the controlled study. I think they are even better,” Prof. Diepgen told delegates. “One reason may be that in the BACH trial, there were limitations on adding other treatments, but in the course of daily practice, other medications can be combined to make therapy more effective. I think alitretinoin is a promising drug and was very surprised that the data were so well reproduced in the real-life environment. ”

Epidermal Barrier Function

Impaired skin barrier function is a key factor in the pathogenesis of eczema. It increases the risk of penetration of irritants and allergens through the skin, thus initiating immunologic reactions and inflammation. Data suggest a possible role of systemic treatment for not only normalizing skin inflammation but also for consolidating epidermal barrier function.

Data suggest alitretinoin down-regulates the immune system and may consolidate epidermal barrier function. To that end, Dr. Mandana Abdollahnia, Department of Dermatology and Allergy, Charité Medical University, Berlin, Germany, investigated the epidermal barrier function by measuring transepidermal water loss (TEWL) and several markers of the peripheral immune response in a 12-week treatment regimen with 30 mg/day.

“TEWL was measured on the back of the hand of 19 patients who had severe standard therapy-refractory CHE of at least 6 months’ duration before, during and after alitretinoin treatment,” Dr. Abdollahnia stated. “TEWL mean values slightly decreased from 22.8 ±5.7 g/hm² before to 19.9 ± 4.3 g/hm² during [week 12] and to 19.4 ± 5.7 g/hm² 4 weeks after the end of alitretinoin treatment. Measurement of peripheral immune responses revealed a significant reduction of IL-17-positive T-cells (P=0.02). Effector T-cell-specific production of other cytokines like IFN-? and IL-4 remained stable. Expression of CD23+ B-cells was decreased (P=0.009) and, accordingly, total serum IgE levels were reduced over time.”

Dr. Abdollahnia concluded that the data imply a possible role for alitretinoin in restoring epidermal barrier integrity and in modulating the immune response. The underlying mechanism of action must await further detailed investigations.