Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

Abstract

Background Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to Th2/Th22 cytokine activation. However, these models have not been tested by in-vivo suppression of T-cell cytokines. CsA is an immune-suppressant highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective To establish the ability of a systemic immune-suppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype, and to correlate changes with clinical improvement. Methods CsA effects on AD skin pathology were evaluated using geneexpression and immunohistochemistry studies in baseline, week 2 and 12 lesional and non-lesional biopsies from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in Scoring of AD/SCORAD. Clinical improvements were associated with significant gene expression changes in lesional but also non-lesional skin, particularly reductions of Th2-, Th22-, and some Th17-related molecules (i.e IL-13, IL-22, CCL17, S100As, elafin/PI3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune-antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

127 Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema

“…Interestingly, PPIA is the cytoplasmic binding partner of cyclosporine, an effective therapeutic in patients with AE. 36 Cyclosporine regulates gene transcription, growth, and differentiation of human keratinocytes, 37 as well as their production of inflammatory cytokines. 38 PPIA knockout mice experience spontaneous T H 2-polarized allergic disease and an immune profile akin to AE, although no dermatitis is reported.…”

Review of Occupational Contact Dermatitis—Top Allergens, Best Avoidance Measures

“…It is imperative to treat with a slow, long taper of at least 3 weeks to avoid a rebound flare. -A recent study suggests that oral cyclosporine can cause alterations in epidermal cell gene expression and can modify cytokine activation [55]. We recommend judicious use of cyclosporine for occupational contact dermatitis due to potential risks associated with treatment.…”

The role of emollients in pathogenetic therapy of atopic dermatitis in children

“…Несмотря на широкую распространенность данного заболевания, в настоящее время отсутствуют гарантированно эффектив-ные методы терапии, особенно тяжелых форм АтД [9,10,15,20,31,34]. Усугубляется это тем, что нередко врачи не учитывают весь комплекс патогенетических механизмов в формировании АтД.…”