Introduction

For almost 40 years now, topical steroids have been the only available agents active against inflammation in atopic dermatitis (AD) or eczema. However, because of their potential to induce thinning of the skin, especially in young children or on sensitive skin areas like face and neck, their use is limited to short courses of therapy (2 to 4 weeks). These short courses are often started when a flare begins. Unfortunately flares are fairly frequent in a chronic disease like AD and an alternative to topical corticoids would be helpful.

A previous study summarized on our site has shown that a new steroid-free cream, pimecrolimus (Elidel®), which has been recently been approved by the FDA, effectively controlled the signs and symptoms of atopic eczema in a 6-week study. Pimecrolimus, targets the inflammatory cells in the skin responsible for itching, redness and swelling associated with atopic eczema. Now a new study extending over a one-year period shows that pimecrolimus reduces the number of disease flares and also decreases or eliminates the need to use topical steroids.

See links below for more information on skin structure, and for the changes seen in atopic eczema.

Study designs and methods of evaluation

The purpose of the study was to compare the effects of two topical creams, identical in appearance: one without (control or placebo treatment) and one with pimecrolimus 1% (active treatment). To be accepted in the study, subjects had to have a score of 2 or greater on the IGA (Investigator Global Assessment) scale and their atopic eczema was to affect at least 5% of their body surface area. The IGA scale had the following grading scores:

0 = Clear; no inflammatory signs of AD
1 = Almost Clear; just perceptible erythema, and just perceptible papulation/infiltration
2 = Mild Disease: mild erythema, and mild papulation/infiltration
3 = Moderate Disease: moderate erythema, and moderate papulation/infiltration
4 = Severe Disease: severe erythema, and severe papulation/infiltration
5 = Very Severe Disease: severe erythema, and severe papulation/infiltration with oozing/crusting

(See link below for signs and symptoms of atopic eczema.)

Allocation to one or the other cream was done randomly using a double-blind method (patients or caregiver and physicians did not know which cream was given). For every 2 patients who received the active preparation, one received the control. The patients were closely monitored for one year after entering the study, with regular visit evaluations done 2, 4, 7, 15, 27, 39 and 53 weeks after first application of study medication. During the whole study, parents (or caregivers) or children had to regularly use emollients for dry skin. A thin film of the study cream was gently applied twice a day on the affected skin areas until there was complete disappearance of signs (such as erythema) or symptoms (such as itching) at the site of application; at this time point study cream administration was stopped. Thereafter, cream application was to be re-started at the first reappearance of signs or symptoms.

It was anticipated that some patients would fare worse under treatment, because of the control group not receiving active anti-inflammatory treatment and also because this is often the case for chronic diseases. This disease worsening pushes the IGA score to higher levels, up to 4 (severe) or even 5 (very severe). If this occurred, a flare was declared to exist, and treatment with a moderately potent topical steroid medication was added, as would be done in normal clinical practice.

The principal measure used to quantify and compare the effects of the two cream preparations was the number of times a flare occurred during the observation period. Since flares were associated with treatment with topical steroid, the frequency and number of steroid treatment days was also computed to compare the two creams.

Safety assessments included records of all adverse events, as well as clinical chemistry and skin immune response to a standard panel of antigens.

Results

A total of 713 patients were randomly allocated to receive pimecrolimus (476) or the control cream (237). The disease severity at the beginning of the trial was similar in the two groups of patients: 26% had mild and 55% moderate AD in the pimecrolimus group, compared to 28 % with mild and 51% with moderate AD in the control group. Severe and very severe AD patients represented 16% and 2.7 % in the pimecrolimus group, compared to 18% and 3.8 % in the control group. The mean age of patients in both groups was 8 years.

Early discontinuation of the study occurred in 51.5 % of the patients given the control, compared with only 31.6 % of those patients given pimecrolimus. The study was interrupted prematurely because of lack of effectiveness in 30% of the patients given the control (placebo), compared to only 12.5% of the patients given the active formulation.

The active cream was given daily for one year in 14% of the 324 patients who completed the 12 months, compared to only 7% of the 115 patients allocated to the control. There were clearly more patient days on pimecrolimus than on control cream, which was related to better effectiveness of the active drug. This was confirmed by the percentage of patients who completed 6 months without any disease flare; this was approximately twice as high in the active group (61%) as in the control group (34%).

At the one year follow up, the percentages completing without a flare were 51% and 28%, respectively. Interestingly, the superiority of the active cream over the control was evident for all grades of disease severity at base line. For example, 60% of pimecrolimus patients having mild disease at base line were free of any flare after one year, compare to only 40% of controls; and 30% of pimecrolimus patients having severe disease at baseline remained free of flares after one year, compared to only 5% of controls.

In the pimecrolimus group, 57% of patients never used topical steroids, whereas about a quarter (25%) used topical steroids for more than 2 weeks. In the control group, 32% of patients never used a topical steroid, but 41% used one for more than 2 weeks.

The overall incidence of adverse events was similar between the two treatment groups, with common childhood infections and ailments being the most commonly reported. The incidence of serious adverse events was low: 8.3% for pimecrolimus and 5.2% for the control group. Bacterial and viral infections occurred in both groups with a similar frequency, but viral skin infections were slightly more frequent in the active group (12.4%) than in the control group (6.3%).

Burning at the application site was reported in 10% of patients given active pimecrolimus cream and in 9% of those given the control cream. The skin response to recall antigens was similar in both groups at the end of the 12 month-period.

Conclusions

The authors conclude that long-term treatment with pimecrolimus 1% cream has "substantial benefits" for patients with atopic eczema. The topical use of pimecrolimus on skin lesions early after their appearance decreases the frequency of flares by approximately 50%, and decreases the need to use a topical steroid preparation, also by 50%. The effect is seen for patients in all groups of disease severity and is sustained up to 12 months. The long-term use of pimecrolimus was well tolerated, and seems to promise better control of atopic eczema.