Background: Topical pimecrolimus may maintain remissions of atopic dermatitis (AD) by inhibiting subclinical inflammation. Objective: To evaluate clinical and cytological effects of pimecrolimus in topical corticosteroid-treated and resolved AD lesions. Methods: Patients (n = 67) with resolved AD lesions were randomized to 3-week double-blind treatment with either pimecrolimus cream 1% or vehicle cream. Outcome measures were reduction in Eczema Area and Severity Index (EASI) and number of leukocytes in skin biopsies in all randomized patients who were evaluable at the end of study. Results: The proportion of patients with a localized EASI <2 at the end of study was higher with pimecrolimus cream 1% than with vehicle cream (73.5 vs. 39.4%, respectively). There was a significant decrease in the number of infiltrating CD45+ cells in pimecrolimus cream 1% compared with placebo cream (–88.2 vs. 43.2 cells/mm2, respectively, p = 0.047) and a slight but nonsignificant reduction in the number of dermal dendritic cells, Langerhans cells, T cells and macrophages with pimecrolimus versus vehicle cream. Limitations: This was an exploratory study. Conclusion: Topical pimecrolimus was effective at maintaining betamethasone-17α-valerate-induced AD remission by inhibiting recurrences of the inflammatory infiltrate in the skin.

Keywords:
Atopic dermatitis, Pimecrolimus cream 1%, Topical corticosteroids, Clinical and cytological response
1.
Leung DYM, Bieber T: Atopic dermatitis. Lancet 2003;361:151–160.
2.
Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA: New insight into atopic dermatitis. J Clin Invest 2004;113:651–657.
3.
Bieber T: Mechanisms of disease: Atopic dermatitis. N Engl J Med 2008;358:1483–1494.
4.
Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R: New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 2006;118:3–21.
5.
Hamid Q, Boguniewicz M, Leung DYM: Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:870–876.
6.
Bratton DL, Hamid Q, Boguniewicz, Doherty DE, Kailey JM, Leung DYM: Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J Clin Invest 1995;95:211–218.
7.
Grewe M, Walther S, Gyufko K, Czech W, Schöpf E, Krutmann J: Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J Invest Dermatol 1995;105:407–410.
8.
Taha RA, Leung DY, Ghaffar O, Boguniewicz M, Hamid Q: In vivo expression of cytokine receptor mRNA in atopic dermatitis. J Allergy Clin Immunol 1998;102:245–250.
9.
Wollenberg A, Kraft S, Hanau D, Bieber T: Immunopharmacological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 1996;106:446–453.
10.
Klubal R, Osterhoff B, Wang B, Kinet JP, Maurer D, Stingl G: The high-affinity receptor for IgE is the predominant IgE-binding structure in lesional skin of atopic dermatitis patients. J Invest Dermatol 1997;108:336–342.
11.
Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, Bieber T: Fcepsilon RI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 2004;113:949–957.
12.
Stary G, Bangert C, Stingl G, Kopp T: Dendritic cells in atopic dermatitis: expression of FcεRI on two distinct inflammation-associated subsets. Int Arch Allergy Immunol 2005;138:278–290.
13.
Bieber T: The pro- and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (Fc epsilon RI). Immunobiology 2007;212:499–503.
14.
Mihm MC, Soter NA, Dvorak HF, Austen KF: The structure of normal skin and the morphology of atopic eczema. J Invest Dermatol 1976;67:305–312.
15.
Novak N, Kraft S, Bieber T: Unraveling the mission of FcεRI on antigen-presenting cells. J Allergy Clin Immunol 2003;111:38–44.
16.
Yawalkar N, Karlen S, Egli F, Brand CU, Graber HU, Pichler WJ, Braathen LR: Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis. J Allergy Clin Immunol 2000;106:941–947.
17.
Wollenberg A, Sharma S, von Bubnoff D, Geiger E, Haberstok J, Bieber T: Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting cells in atopic dermatitis. J Allergy Clin Immunol 2001;107:519–525.
18.
Simon D, Vassina E, Yousefi S, Kozlowski E, Braathen LR, Simon HU: Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment. J Allergy Clin immunol 2004;114:887–895.
19.
Hoetzenecker W, Ecker R, Kopp T, Stuetz A, Stingl G, Elbe-Bürger A: Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis. J Allergy Clin Immunol 2005;115:1276–1283.
20.
Simon D, Vassina E, Yousefi S, Braathen LR, Simon HU: Inflammatory cell numbers and cytokine expression in atopic dermatitis after topical pimecrolimus treatment. Allergy 2005;60:944–951.
21.
Stuetz A, Baumann K, Grassberger M, Wolff K, Meingassner JG: Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus. Int Arch Allergy Immunol 2006;141:199–212.
22.
Hultsch T, Kapp A, Spergel J: Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Dermatology 2005;211:174–187.
23.
Hengge UR, Ruzicka T, Schwartz RA, Cork MJ: Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006;54:1–15.
24.
Kapp A, Papp K, Bingham A, Foelster-Holst R, Ortonne J-P, Potter PC, Gulliver W, Paul C, Molloy S, Barbier N, Thurston M, de Prost Y, Flare Reduction in Eczema with Elidel (Infants) Multicenter Investigator Study Group: Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110:277–284.
25.
Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, de Prost Y, Flare Reduction in Eczema with Elidel (Children) Multicenter Investigator Study Group: Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110:1–8.
26.
Meurer M, Foelster-Holst R, Wozel G, Weidinger G, Juenger M, Braeutigam M, CASM-DE-01 Study Group: Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology 2002;205:271–277.
27.
Siegfried E, Korman N, Molina C, Kianifard F, Abrams K: Safety and efficacy of early intervention with pimecrolimus cream 1% combined with corticosteroids for major flares in infants and children with atopic dermatitis. J Dermatol Treat 2006;17:143–150.
28.
Gollnick H, Kaufmann R, Stough D, Heikkila H, Andiano K, Grinienko A, Jimenez P: Pimecrolimus cream 1% in the long-term management of adult atopic dermatitis: prevention of flare progression. A randomized trial. Br J Dermatol 2008;158:1083–1093.
29.
Sigurgeirsson B, Ho V, Ferrándiz C, Andriano K, Grinienko A, Jimenez P: Effectiveness of a prevention-of-flare progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol 2008;22:1290–1301.
30.
Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;92:S44–S47.
31.
Graham-Brown RAC, Grassberger M: Pimecrolimus: a review of pre-clinical and clinical data. Int J Clin Pract 2003;57:319–327.
32.
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M: The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol 2001;10:11–18.
33.
Steiner GE, Ecker RC, Kramer G, Stockenhuber F, Marberger MJ: Automated data acquisition by confocal laser scanning microscopy and image analysis of triple stained immunofluorescent leukocytes in tissue. J Immunol Methods 2000;237:39–50.
34.
Ecker RC, Rogojanu R, Streit M, Oesterreicher K, Steiner GE: An improved method for discrimination of cell populations in tissue sections using microscopy-based multicolor tissue cytometry. Cytometry A 2006;69:119–123.
35.
Laberge S, Ghaffar O, Boguniewicz M, Center DM, Leung DY, Hamid Q: Association of increased CD4+ T-cell infiltration with increased IL-16 gene expression in atopic dermatitis. J Allergy Clin Immunol 1998;102:645–650.
36.
Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB, Leung DY: Cytokine milieu of atopic dermatitis, as compared to psoriasis, prevents induction of innate immune response genes. J Immunol 2003;171:3262–3269.
37.
Nomura I, Gao B, Boguniewicz M, Darst MA, Travers JB, Leung DY: Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J Allergy Clin Immunol 2003;112:1195–1202.
38.
Leung DYM, Bhan AK, Schneeberger EE, Geha RS: Characterization of the mononuclear cell infiltrate in atopic dermatitis using mononuclear antibodies. J Allergy Clin Immunol 1983;71:47–56.
39.
Wolkerstorfer A, Strobos MA, Glazenburg EJ, Mulder PJ, Oranje AP: Fluticasone propionate 0.05% cream once daily versus clobetasone butyrate 0.05% cream twice daily in children with atopic dermatitis. J Am Acad Dermatol 1998;39:226–231.
40.
Hayashi R, Wada H, Ito K, Adcock IM: Effects of glucocorticoids on gene transcription. Eur J Pharmacol 2004;500:51–62.
41.
Stellato C: Post-transcriptional and nongenomic effects of glucocorticoids. Proc Am Thorac Soc 2004;1:255–263.
42.
von Bubnoff D, Geiger E, Bieber T: Antigen-presenting cells in allergy. J Allergy Clin Immunol 2001;108:329–339.
43.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YS, Pulendran B, Palucka K: Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767–811.
44.
Woods GM, Malley RC, Muller HK: The skin immune system and the challenge of tumour immunosurveillance. Eur J Dermatol 2005;15:63–69.
45.
Kalthoff FS, Chung J, Stuetz A: Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogenic dendritic cells. Clin Exp Immunol 2002;130:85–92.
46.
Kwiek B, Peng W-M, Allam J-P, Langner A, Bieber T, Novak N: Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells. J Allergy Clin Immunol 2008;122:126–132.
47.
Al-Daraji WI, Grant KR, Ryan K, Saxton A, Reynolds NJ: Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A. J Invest Dermatol 2002;118:779–788.
48.
Büchau AS, Schauber J, Hultsch T, Stuetz A, Gallo RL: Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes. J Invest Dermatol 2008;128:2646–2654.
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