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.