A Safety Assessment of Topical Calcineurin Inhibitors in the Treatment of Atopic Dermatitis

Mark Lebwohl, MD; Tara Gower, PhD


October 10, 2006

TCIs for Treatment of AD

The safety and efficacy of TCIs have been studied extensively in children and adults with AD in short- and long-term trials.[13,14] TCIs target the underlying inflammatory pathogenesis of AD. They bind macrophilin-12 (FKBP-12) and inhibit calcineurin activity, preventing the nuclear translocation of nuclear factor-activated T cells.[15] As a result, T-cell activation and the subsequent production and release of proinflammatory cytokines are inhibited.[15] In addition, TCIs have been shown to inhibit the release of proinflammatory mediators from mast cells.[15,16,17] This inhibition of the inflammatory response of AD reduces eczema symptoms, including pruritus.[13,14]

Tacrolimus Ointment 0.03% and 0.1%

In the United States, tacrolimus ointment 0.03% and 0.1% is indicated for adults, whereas tacrolimus ointment 0.03% is indicated for children aged 2-15 years. The indication, which was revised in January 2006, states that tacrolimus should be used as second-line therapy for short-term and noncontinuous chronic treatment of moderate-to-severe AD in nonimmunocompromised adults and children aged ≥ 2 years who have failed to respond adequately to other topical prescription treatments or when those treatments are not advisable.[12] Several studies in children and adults have demonstrated that tacrolimus ointment effectively reduces the frequency of AD flares and treats the disease (measured by the Investigator's Global Assessment [IGA] score) as well as its accompanying symptoms (Figure 2).[18,19,20,21,22,23] A head-to-head comparison with topical corticosteroids showed comparable efficacy between tacrolimus ointment 0.1% and the midpotency corticosteroid hydrocortisone butyrate 0.1%.[24] A similar comparison in children showed that tacrolimus ointment (0.03% and 0.1%) was more effective than the over-the-counter corticosteroid hydrocortisone acetate 1%.[25]

Pimecrolimus Cream 1%

Similarly, pimecrolimus cream 1% is indicated as second-line therapy for the short-term and noncontinuous chronic treatment of mild-to-moderate AD in nonimmunocompromised adults and children aged ≥ 2 years who have failed to respond adequately to other topical prescription treatments or when those treatments are not advisable.[11] In clinical trials, pimecrolimus cream 1% was significantly more effective in treating the symptoms of eczema compared with vehicle cream.[26,27,28,29] Clinical studies have also demonstrated that early treatment with pimecrolimus cream 1% significantly increases the time between flares (defined as disease that requires treatment with a topical corticosteroid), reduces the frequency of flares, and reduces the need for topical corticosteroids (Figure 3).[27,28] In head-to-head trials comparing pimecrolimus cream 1% with topical corticosteroids (eg, 0.1% betamethasone-17-valerate cream, 0.1% triamcinolone acetonide cream, or 1% hydrocortisone acetate), pimecrolimus was well tolerated and effectively treated AD symptoms.[30,31] Two studies by Luger and colleagues,[30,31] in patients with moderate-to-severe AD, showed that pimecrolimus cream 1% was not more effective than the topical corticosteroids, although pimecrolimus was an effective corticosteroid-sparing drug. In these studies, approximately 42% of patients who were treated with pimecrolimus were successfully maintained for 1 year without using topical corticosteroids.[30,31]

Figure 3.

Percentage of patients in a 6-month study in adults (N = 192) and a 1-year study in children aged 2-17 years (N = 713) who were treated with pimecrolimus cream 1% who had no flares throughout the entire study period compared with patients in the control group who were treated with vehicle cream. Adapted with permission from Dermatology and Pediatrics.[27,28] Copyright 2002, American Academy of Pediatrics. Copyright 2005, Karger.


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