Topical Noncorticosteroid Immunomodulation in the Treatment of Atopic Dermatitis

Abstract

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/ pimecrolimus-FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells. The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been observed. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This again results in reduced bioavailability of the drug, as compared with systemic use. Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus (at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at the site of application. Typically, these adverse events are observed only during the first days of treatment. Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis.

Comparative Effect of Tacrolimus and Betamethasone Valerate on the Passive Sustainable Hydration of the Stratum Corneum in Atopic Dermatitis

“…For many years, topical corticosteroid therapy remained the standard of care [36, 37] but the new topical calcineurin inhibitors have opened a new pharmacological era in this field [1, 2,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. The effect of theses drugs on the functional properties of atopic skin have not been thoroughly explored so far.…”

“…Moderate to severe refractory atopic dermatitis is the major indication of topical tacrolimus [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. In this condition, the primary target is the inflammatory cells including the T lymphocytes and Langerhans cells.…”

Glucocorticoids for Human Skin: New Aspects of the Mechanism of Action

“…Studies in rheumatoid synovial [54] and murine skin fi broblasts [79] also indicate a synergistic effect of tacrolimus and low-dose dexamethasone which may translate into clinical improvement. Due to the still measurable potential for skin atrophy of glucocorticoids and the lower potency and the risk of photocarcinogenesis with tacrolimus and pimecrolimus [80] , a combination therapy that is safe and effective in longterm treatment of severe cases would be welcome.…”

Mechanism of Action and Emerging Role of Immune Response Modifier Therapy in Dermatologic Conditions

“…94 Pimecrolimus is structurally similar to tacrolimus and also binds to macrophilin 12, with a three-fold lower binding affinity compared with tacrolimus. 95 Thus, it also acts to prevent calcineurin dephosphorylation of NF-AT. Pimecrolimus also prevents the release of cytokines and proinflammatory mediators from mast cells.…”