Atopic Dermatitis Knowledge Centre
Pharmacological
Topical calcineurin inhibitors
Calcineurin inhibitors are immunosuppressant agents originally developed, in the case of tacrolimus, for systemic administration to prevent allogeneic transplant rejection. Topical formulations of tacrolimus and pimecrolimus were developed as alternatives to topical corticosteroids and are the only two drugs of this class currently licensed for the treatment of atopic dermatitis.
Tacrolimus and pimecrolimus have a distinct mechanism of action from that of the corticosteroid drugs when administered topically. Treatment with these agents results in a transcriptional blockade of inflammatory cytokines released from activated T-cells, through the inhibition of the phosphatase enzyme, calcineurin. As discussed in the Understanding Atopic dermatitis section of this knowledge base, T-cell activation is a critical factor in the pathophysiology of the condition contributing significantly to the inflammatory response to allergens. Interruption of T-cell activation in the epidermis significantly reduces the skin’s inflammatory response in atopic dermatitis and there is substantial clinical evidence demonstrating that topical calcineurin inhibitors effectively inhibit T-cell responses and also prevent the release of inflammatory modulators from mast cells and basophils . The mechanism of action of topical calcineurin inhibitors target the signs and symptoms of atopic dermatitis more specifically than topical corticosteroids.
Topical calcineurin inhibitors are currently licensed for use in patients aged 2 years and older who do not respond to topical corticosteroid treatments, or where there is a serious risk of adverse effects from continued topical corticosteroid use.3 Initially indicated for the short-term treatment of acute flares, these drugs are not associated with the side-effects commonly reported after topical corticosteroid use. Clinical efficacy of tacrolimus 0.1% ointment in adults is superior to that of a standard corticosteroid regimen, 1% hydrocortisone acetate on the head and neck, and 0.1% hydrocortisone butyrate on the trunk and limbs.13 In addition, the clinical efficacy of tacrolimus 0.03% ointment in children is superior to 1% hydrocortisone acetate.14 Furthermore, topical calcineurin inhibitors are associated with fewer, and less severe local and systemic adverse effects. Recently, topical calcineurin inhibitors have been reviewed by the regulators to determine if the use of these products is associated with an increased risk of malignancy. This theoretical risk was based on data from systemic exposure to calcineurin inhibitors prescribed to transplant patients. Thus far there is no evidence of an increased risk of malignancy associated with tacrolimus ointment.15–18 The principle side-effect reported after tacrolimus or pimecrolimus use is local irritation at the site of application.19
In addition to the indication for the treatment of acute flares of atopic dermatitis, a twice-weekly regimen with topical tacrolimus ointment (but not pimecrolimus cream) has now been approved in Europe to prevent flares and prolong flare-free periods in patients with moderate or severe disease who experience at least 4 flares a year.20 After flare resolution with twice-daily tacrolimus ointment, twice-weekly use of tacrolimus in previously inflamed skin has been shown to reduce the frequency of flares and significantly prolong the time to first flare in adults and children (aged 2 years and older) with moderate and severe atopic dermatitis.20
References:
3. Eichenfield LF. Consensus guidelines in diagnosis and treatment of atopic dermatitis. Allergy 2004; 59 Suppl 78: 86–92.
13. Reitamo S, Ortonne JP, Sand C, et al. A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 2005; 152: 1282–9.
14. Reitamo S, Van Leent EJ, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002; 109: 539–46.
15. Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007; 127: 808–16.
16. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology 2007; 214: 289–95.
17. Naylor M, Elmets C, Jaracz E, et al. Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatolog Treat 2005; 16: 149–53.
18. Rustin MH. The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br J Dermatol 2007; 157: 861–73.
19. Lebwohl M, Gower T. A safety assessment of topical calcineurin inhibitors in the treatment of atopic dermatitis. MedGenMed 2006; 8: 8.
20. PROTOPIC – Summary of Product Characteristics. Available from: http:/anti-infectives/Paris-Event/Live-Webcast.cfmwww.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000374/WC500046824.pdf [Accessed July 2010].
© February 2010 Astellas Pharma Europe LTD.
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