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.

21st World Congress of Dermatology

Buenos Aires, Argentina / September 30 - October 5, 2007

The single most pressing concern for patients with atopic dermatitis is rapid relief of itch. As the patient scratches, the skin becomes more susceptible to recurring infections. This is particularly a problem during sleep, when conscious control of scratching decreases and the absence of other outside stimuli makes the itchiness more noticeable. As noted by Dr. Alan Fleischer, Jr., Professor and Chair, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, a study from Asia recently found that the symptom of itching diminished before any improvement from treatment was reported in the percentage of body surface area affected or in the Eczema Area and Severity Index (EASI). “Itch is the cardinal symptom,” remarked Dr. Fleischer. “People ‘chronitize’ the disease by scratching.”

Treatment of Atopic Dermatitis: A Review

During an interactive question-and-answer session with his audience, Dr. John Harper, Great Ormond Street Hospital for Children, London, UK, concurred with the majority response that between 11% and 25% of atopic dermatitis patients receiving corticosteroid treatment would be candidates for treatment with a calcineurin inhibitor. “That’s probably about right, based on what I see in my own practice,” he observed. In discussing the extensive research program which led to the licencing of tacrolimus ointment for second-line treatment of patients with moderate and severe atopic dermatitis, Dr. Harper reviewed four large, randomized trials, two involving children and two adults.

He first summarized results of two similarly designed three-week, randomized, double-blind trials involving a total of 1184 children between the ages of 2 and 15 years with moderate to severe atopic dermatitis. The results of the first study in 560 patients indicated that both 0.03% and 0.1% tacrolimus ointment twice daily were significantly more effective than twice-daily hydrocortisone acetate 1% ointment, as measured by the modified EASI (mEASI). The only adverse effect to show a significantly higher incidence in the tacrolimus group was skin burning, which manifested in the early treatment stages and subsided rapidly (J Allergy Clin Immunol 2002;109(3):539-46). The second study (624 patients) demonstrated significantly greater improvement with 0.03% tacrolimus ointment once (P<0.001) or twice daily (P<0.015) vs. twice-daily hydrocortisone acetate 1%. Dr. Harper noted that the best results in this trial were seen with tacrolimus applied twice daily. Again, the most significant adverse effect was transient burning, which subsided quickly (Br J Dermatol 2004; 150(3):554-62).

Dr. Harper next looked at treatment of adults. He cited a comparative study in 570 adult patients with moderate to severe atopic dermatitis in which treatment with 0.03% and 0.1% tacrolimus was compared to 0.1% hydrocortisone-17-butyrate ointment, a mid-potent to potent corticosteroid, over a three-week period. It was found that tacrolimus 0.1% applied twice daily was as effective as hydrocortisone butyrate 0.1% ointment twice daily with similar improvements on the itch scale. Both the 0.1% calcineurin inhibitor and hydrocortisone butyrate 0.1% formulations provided better results than the 0.03% calcineurin inhibitor. Adverse effects included transient skin burning and pruritus at the application site (J Allergy Clin Immunol 2002;109(3):547-55).

The fourth multicentre, randomized, double-blind, controlled study followed 972 adults with moderate to severe atopic dermatitis for six months. Treatment consisted of twice-daily applications of tacrolimus 0.1% or a regimen of hydrocortisone butyrate 0.1% to the trunk and limbs, and hydrocortisone acetate 1% to the face and neck (Br J Dermatol 2005;152(6):1282-9). On all dates measured, including as early as day 8, tacrolimus 0.1% was found to be substantially more effective than the steroid regimen according to the primary end point of a 60% improvement in the mEASI (P<0.001), as well as by subjective assessments by both doctors and patients. Again, the most common adverse effect was skin burning, which subsided rapidly after one week of treatment.

Trials of Calcineurin Inhibitors

Dr. Richard J. Antaya, Director, Yale Dermatology Associates and Director, Pediatric Dermatology, and Associate Professor, Yale University School of Medicine, New Haven, Connecticut, reviewed results from three multicentre, randomized, investigator-blinded studies of six weeks’ duration which compared the effectiveness and safety of tacrolimus ointment and pimecrolimus cream in the treatment of patients with mild to very severe atopic dermatitis. These trials involved a total of 1065 individuals, including children over two years old and adults. As measured by a reduction in EASI, a 53% improvement from baseline was shown in patients treated with tacrolimus compared to 39% for those using pimecrolimus (P<0.0001). When defined as “clear” or “almost clear” on the Investigator Global Atopic Dermatitis Assessment, 43% of patients using tacrolimus achieved treatment success compared to 31% for pimecrolimus (P<0.0001). The change in percentage of body surface area affected was 54% for tacrolimus-treated patients compared to 41% for pimecrolimus (P<0.0001). Discontinuation rates due to lack of efficacy were 2.5% and 6.6% in the tacrolimus and pimecrolimus cohorts, respectively (P<0.001). The number of patients who reported adverse effects were about equal: 21% for tacrolimus vs. 20% for pimecrolimus, with skin burning (11% tacrolimus, 10% pimecrolimus) and itching (both 7%) being the most common (J Am Acad Dermatol 2005;52(5):810-22). According to Dr. Antaya, differences in burning sensation were not statistically significant. “As the severity of the disease increases, there is more burning, which is more common with tacrolimus. With adults, by day 8 it is similar.”

Long-term Safety and Efficacy Data

Dr. Fleischer observed that data on the safety and efficacy of tacrolimus has now been analyzed from numerous post-approval studies involving some 10,000 children and adults with atopic dermatitis. The improvement among patients in these studies has been “rapid and continued for the duration”; safety results have not changed over four years and there has been no increase in adverse effects over time. Indeed, the highest percentage of skin infections is reported in the first year of use. “The theory is that the skin’s natural protection improves as the condition improves,” thereby becoming less susceptible to infections, Dr. Fleischer explained. He also noted that patients with more severe atopic dermatitis report more burning due to therapy at all points in time, but this problem tends to diminish with treatment. Dr. Fleischer also refuted reports of increased cancer risk, stating, “There is no evidence that there is a greater risk of lymphoma with this class of drug.”

According to Dr. Fleischer, given the need for longer-term studies, some 2000 children with a history of atopic dermatitis have been enrolled in a prospective, multinational, longitudinal research project in which the children will be followed for 10 years. Preliminary results of this trial confirm the safety of tacrolimus ointment.

Its long-term effectiveness and safety in preventing flare-ups of atopic dermatitis has also been studied, he reported. In a recent maintenance study of 195 patients with stabilized atopic dermatitis, the efficacy of three-times-weekly application of tacrolimus for 40 weeks was evaluated for the prevention of relapse. Corticosteroid therapy was not permitted, even during relapse.

Findings indicated that tacrolimus maintenance therapy (n=124) resulted in more flare-free days compared with using it only when a flare recurs (n=71) (177.47 days vs. 134.1 days, respectively; P=0.003). Median time to first relapse was significantly longer at 169 days vs. 43 days (P<0.037). No difference in the occurrence of application-site burning or itching was observed (maintenance therapy 8.0%, therapy at recurrence 8.5%). The study also revealed that the total quantity of tacrolimus used by patients who applied the ointment two or three times a week as a form of prevention was less than that used by patients who only resumed use during a flare.

Summary

Experts here reviewed the substantial body of research that supports the safety and efficacy of tacrolimus as second-line treatment for moderate to severe atopic dermatitis, including its effectiveness in treating itch, the primary symptom reported by patients with this condition. They also discussed the growing evidence to support the use of this agent as maintenance or preventive therapy in atopic dermatitis, where its use can help to increase the number of flare-free days and limit the need for long-term corticosteroid therapy.