Chapter 4. Topical Calcineurin Inhibitors
Topical calcineurin inhibitors are a relatively new class of non-steroidal immunomodulators. By inhibiting the enzyme calcineurin in immune cells, they interfere with the production of a number of inflammatory mediators that participate in skin inflammation in atopic dermatitis. They have also been shown to inhibit release of histamine from cells such as mast cells and basophils. Calcineurin inhibitors act through steroid receptor-independent pathways and thus even chronic use does not result in any steroid side effects. They are approximately twice the size of corticosteroids molecules, which likely contributes to their safety profile. Topical calcineurin inhibitors were developed after beneficial effects were observed in transplant patients with concomitant psoriasis or eczematous rashes treated with systemic cyclosporin A and tacrolimus, potent inhibitors of T-cells. Subsequently, a topical preparation of cyclosporin A was shown not to be clinically useful presumably due to its large molecular size (approximately 3 times that of corticosteroids, and 1 and 1/2 times that of tacrolimus).
Preliminary clinical studies with tacrolimus in an ointment base, on the other hand, showed that concentrations of 0.03% and 0.1% were both safe and effective. Extensive studies were carried out in Japan, the United States and Europe. In the United States, children as young as 2 years of age with moderate-to-severe atopic dermatitis with extensive body surface area involvement were enrolled in long-term studies. Burning or stinging at the site of application was the only frequently noted adverse event and this tended to diminish over the first 3-4 days in parallel with clinical improvement. Tacrolimus ointment marketed by Fujisawa Healthcare Inc. as Protopic® 0.03% for children 2 to 15 years of age and 0.03% and 0.1% for adults has been approved by the Food and Drug Administration for short-term and intermittent long-term use in moderate-to-severe atopic dermatitis. Since atopic dermatitis is a chronic disease, long-term open studies with tacrolimus ointment applied on up to 100% BSA have been performed for up to 12 months in adults and children without a suggestion of tachyphylaxis or increase in skin infections. In fact, S. aureus colonization has been shown to decrease during long-term therapy with tacrolimus ointment. In addition, unlike topical corticosteroids, tacrolimus ointment does not cause cutaneous atrophy and has been used for facial and eyelid eczema. Long term monitoring of patients treated with tacrolimus ointment has created a global database of over 13,000 patients worldwide, and safety and efficacy data are available for up to four years of tacrolimus use in atopic dermatitis.
Pimecrolimus is a newer calcineurin inhibition, developed specifically to treat inflammatory skin conditions. Pimecrolimus cream 1% has been shown to be effective for atopic dermatitis with little systemic absorption. As with tacrolimus ointment, treatment of facial eczema including periocular dermatitis was well tolerated. Burning and stinging reported with pimecrolimus has been lower than with vehicle cream. Pimecrolimus (Elidel®) cream 1% (marketed by Novartis Pharmaceutical Corporation) has been approved by the Food and Drug Administration for use in patients ≥2 years of age with mild to moderate atopic dermatitis. It has been studied extensively in children with atopic dermatitis in large multicentered controlled trials with application twice daily for up to 12 months. While not approved by the Food and Drug Administration for use in children less than two years of age, several studies of pimecrolimus 1% cream have been performed in this age group showing excellent tolerance as well as clinical benefit, including rapid and sustained resolution of pruritus.
In a novel approach to treating a chronic, often relapsing inflammatory skin disease such as atopic dermatitis, early intervention with pimecrolimus 1% cream at the first signs and symptoms of disease activity such as erythema or pruritus and need for “rescue” topical steroid therapy to treat flares of atopic dermatitis was assessed. Trials performed in children included a large number of infants three months to two years of age. Patients were treated twice daily with the study medication for up to 12 months. A significant number of infants and children including those with mild, moderate and even severe atopic dermatitis treated with pimecrolimus cream never required any topical corticosteroids during the study.
It is reassuring that no significant increase in viral infections such as eczema herpeticum has been observed for the group of patients treated with topical calcineurin inhibitors. In addition, no significant increase in non-melanoma skin cancers has been documented. As a precaution and practical skin care recommendation, patients should be encouraged to use sunscreens. Long-term monitoring of patients on this new class of non-steroidal therapy should continue to gather further experience. Of note, no such long-term evaluation of topical corticosteroids has been performed.