Molecular signatures order the potency of topically applied anti-inflammatory drugs in atopic dermatitis patients

Publication date: Available online 24 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Emma Guttman-Yassky, Benjamin Ungar, Kunal Malik, Daniel Dickstein, Maria Suprun, Yeriel D. Estrada, Hui Xu, Xiangyu Peng, Margeaux Oliva, Dan Todd, Tord Labuda, Mayte Suarez-Farinas, Robert Bissonnette
BackgroundAtopic Dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in psoriasis, another common inflammatory disease, to assess efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis.ObjectiveWe aimed to assess changes in molecular signatures of intra-patient target lesions treated with topical therapeutics.MethodsWe enrolled 30 mild-to-moderate AD patients in a randomized, double-blinded, intra-individual comparison of 3 approved agents applied blindly at the investigator site daily for 14d: pimecrolimus, betamethasone diproprionate, clobetasol proprionate, and a vehicle/emollient control. Changes in total sign scores (TSS), trans-epidermal water loss (TEWL), and tissue biomarkers (using RT-PCR and immunohistochemistry) were evaluated.ResultsTSS showed improvements of 30%, 40%, 68%, and 76% at 2wks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in TEWL (p<0.05). Significant differences vs. vehicle were limited to steroids (p<0.0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation vs. minimal changes with vehicle or pimecrolimus (p<0.001). Cellular infiltrates and cytokines (IL-13, IL-22, S100As) were similarly reduced only by steroids (p<0.001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers.ConclusionWe detected significant clinical and tissue differences between agents, providing a novel approach to study differential effects of topical formulations using a limited sample size.

Teaser

Our novel intra-patient evaluation of topical formulations found pronounced differences in biomarker responses between steroids, pimecrolimus, and emollient. While clinical and mechanistic data were congruent, the tissue analyses provided higher differentiation between various products.


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