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.

15th Congress of the European Academy of Dermatology and Venereology

Rhodes, Greece / October 4-8, 2006

Atopic dermatitis (AD) is a chronic inflammatory skin disease with potentially serious complications. The overall estimated prevalence is 10% in Canada. While the cost to treat an individual case of AD is relatively low, between $300 and $1200 annually, its prevalence leads to high health care costs for Canada, estimated in 2006 at $1.4 billion per year.

Treatment includes both healing the skin and preventing additional AD flares. Acute outbreaks of AD are often treated with topical corticosteroids. However, AD frequently requires long-term treatment, and extended use of topical corticosteroids has been linked to serious side effects, including skin atrophy, adrenocortical insufficiency and glaucoma.

The topical calcineurin inhibitor (TCI) tacrolimus appears to suppress early T-cell activation without affecting collagen synthesis or skin thickness. The ointment formulation has been shown effective in treating AD in both adult and pediatric populations.

Long-term Treatment of AD

Dr. Sakari Reitamo, Department of Dermatology, Helsinki University Central Hospital, Finland, summarized both the current concerns about TCIs and available long-term efficacy data. He also presented details of the safety and efficacy results from CONTROL (Clinical Study on Tacrolimus Ointment Over the Long Term in Adults) and provided recent data from a study of the pharmacokinetics of topical tacrolimus in young children.

The European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) have expressed concerns about possible immunosuppression during long-term management of AD with either tacrolimus or a related agent, pimecrolimus. As Dr. Reitamo explained, the EMEA informed patients and health care professionals that the benefits associated with TCIs currently outweigh the known risks, and that it was unable to conclude definitively whether these agents caused the reported cases of skin cancer or lymphoma. He noted that the FDA currently recommends tacrolimus ointment and pimecrolimus as second-line agents for short-term and intermittent long-term treatment of AD.

Dr. Reitamo reminded the audience that extremely low systemic exposure has been demonstrated in patients after topical administration of tacrolimus ointment. He reviewed additional data on tacrolimus safety from a pediatric phase III trial (Remitz et al. Acta Dermato-Venereologica 2006; in press). The authors reported a very low prevalence of viral infections (varicella zoster, herpes simplex and warts) at tacrolimus application sites in children. These data were compiled during three-month intervals over the course of 18 months.

Dr. Reitamo also examined tacrolimus ointment efficacy and safety results from a phase III study comparing tacrolimus ointment (0.1%) to a mid-potency topical corticosteroid regimen in adults with AD (Reitamo et al. Br J Dermatol 2005;152(6):1282-9). Patients in the tacrolimus treatment group (n=487) applied the TCI ointment to all affected areas. Patients in the corticosteroid arm (n=485) applied 0.1% hydrocortisone butyrate ointment to affected areas on the trunk and extremities and 1% hydrocortisone acetate ointment to affected areas on the face and neck. Treatment was applied twice daily for a maximum of six months. The study’s primary end point was the proportion of patients with at least 60% improvement in the modified Eczema Area and Severity Index (mEASI) between baseline and month 3. Long-term treatment with tacrolimus ointment provided sustained, superior results to corticosteroids at this end point (P<0.001 at all time points). The authors reported no increase in the incidence of infections or malignancies in either treatment group during the trial.

Topical treatment with tacrolimus may also prove advantageous in the treatment of other atopic symptoms, Dr. Reitamo noted. He cited data from a retrospective study that indicate promising results for the TCI ointment as a treatment for severe atopic blepharoconjunctivitis (Virtanen et al. Acta Ophthalmol Scand 2006;84(5):693-5).

Results from an analysis of lymphoma risk and exposure to TCIs and topical steroids were also discussed here at the EADV. Arellano and colleagues performed a nested case-control analysis to evaluate the association between topical immunosuppressants and lymphoma in a cohort with AD. Each case of lymphoma in the cohort of nearly 300,000 AD patients was matched randomly with four controls with similar length of follow-up. The authors did not find an increased risk of lymphoma in patients treated with TCIs. The severity of AD was the principal factor associated with an increased risk of lymphoma, while steroids appeared to increase the risk to a lesser degree (Arellano et al. J Invest Dermatol DOI:10.1038/sj.jid.5700622).

CONTROL Results

Dr. Reitamo delved into detail about the CONTROL study in a separate presentation during the scientific sessions. CONTROL was a multicentre, double-blind, randomized phase III study designed to compare the efficacy and safety of tacrolimus ointment (0.1%) to placebo for the control of AD in adults. Two hundred fifty-seven patients, including those with mild, moderate or severe AD, were enrolled in an initial one- to six-week, open-label regimen of twice-daily ointment. Tacrolimus ointment was well tolerated and effective in all AD severities during this period.

Patients were then randomly assigned to active treatment or control (placebo) group. They used either active ointment or placebo, one application twice a week, for 12 months. During disease exacerbation periods, patients used twice-daily tacrolimus. Exacerbations lasting more than six weeks led to study discontinuation.

The primary study end point was the number of disease exacerbations during the disease control period that required a “substantial therapeutic intervention,” as defined by the study protocol. Secondary end points included time to first exacerbation, Investigators’ Global Assessment (IGA) score and the Dermatology Life Quality Index score.

The number of disease exacerbations requiring intervention was significantly lower in the active treatment arm than the placebo arm, regardless of disease severity. Time to the first exacerbation was significantly longer in the tacrolimus ointment arm, and results were similar in all stratifications by AD severity. The percentage of patients with an IGA score >2 was consistently lower in the treatment arm and similar benefits were seen for other efficacy parameters for all AD severities. The number of treatment-related adverse events was similar in both arms, despite longer treatment follow-up in the tacrolimus ointment arm, and most events were mild or moderate. Only two serious adverse events were considered treatment-related, one in each arm. The researchers also noted that the total amount of ointment applied in patients with moderate or severe AD was not increased in the treatment cohort.

The CONTROL study is the first to demonstrate that a maintenance regimen with topical tacrolimus ointment (0.1%) can help to manage AD successfully over the long term.

Pediatric Pharmacokinetics

Dr. Reitamo summarized a study of the systemic exposure to tacrolimus ointment (0.03%) in pediatric AD patients aged three months to two years. This was a phase II, multicentre, randomized, double-blind study. Patients were randomized to once-daily (n=24 patients) or twice-daily (n=22 patients) treatment. Serial blood samples were taken on day 1 (first ointment application) and day 14, the final day of application, to evaluate the pharmacokinetics of the active agent. Systemic exposure to tacrolimus was found to be minimal, with most (>95%) blood samples showing absorption of <1 ng/mL.

Summary

AD is a significant health concern in both children and adults. There had been concerns that treatment of AD with the newer immunosuppressive agents tacrolimus or pimecrolimus may lead to the development of skin cancers and lymphomas. Dr. Reitamo presented recent data from several studies supporting the safety and efficacy of tacrolimus in both pediatric and adult populations.