Topical Immunomodulation in atopic dermatitis

Topical corticosteroids are effective for the treatment of atopic dermatitis when used short-term. Their long-term use is associated with many side-effects such as atrophy of the skin, resistance to therapy, or even retardation of growth in children. Therefore, new alternatives for the treatment of atopic dermatitis and other corticosteroid-responsive skin diseases are needed. The first in a new class of topical immunomodulatory agents is tacrolimus (FK506, Protopic^®), followed by pimecrolimus (ASM 981, Elidel^®). These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP). The binding affinity to this receptor determines the relative clinical efficacy of these compounds. 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 inhibition of the translocation of NF-ATp (the nuclear factor for activated T cell protein) to the nucleus. This leads to an inhibition of activation of T cells at an early stage. Tacrolimus but not pimecrolimus has been shown to possess inhibitory effects on antigen-presenting cells, such as the Langerhans cells and inflammatory epidermal dendritic cells. The inhibitory effects on mast cells and basophils has been shown for both tacrolimus and pimecrolimus. placebo-controlled studies in atopic dermatitis have shown the efficacy of both tacrolimus and pimecrolimus. As these compounds lack suppressive effects on connective tissue, treatment of inflammation can lead to total healing of the skin. This again results in reduced or absent bioavailability of the drug. The main adverse event in these studies has been a burning and increased pruritus sensation at the site of application. Long-term safety studies of have not revealed any new adverse events. Evidence from recent studies with tacrolimus suggest that monotherapy is preferable to combination therapy with corticosteroids. The topical immunomodulatory agents could replace corticosteroids as first-line treatment of atopic dermatitis. Topical immunomodulation could also prove to be useful for other types of eczema and also other inflammatory skin disorders such as some forms of psoriasis, vitiligo, oral lichen planus and ulcers associated with in rheumatoid arthristis and pyoderma gangrenosum.