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Circulating Monocytes are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast

ABSTRACT: Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of psoriasis patients. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyper-adhesive monocyte doublets at baseline were more likely to be responders to apremilast (p< 0.0001); 82% of subjects with elevated hyper-adhesive monocyte doublets achieved 50% reduction in PASI (PASI50) compared to 46% in those without elevated doublets. We observed a significant reduction in hyper-adhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially-expressed gene transcripts predictive of clinical response uncovered pharmaco-endotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness, and to develop an apremilast psoriasis treatment algorithm using monocyte refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256275 | GEO | 2024/02/26

REPOSITORIES: GEO

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Project description:FelixGarza2017 - Blue Light Treatment of Psoriasis (simplified) This model is described in the article: A Dynamic Model for Prediction of Psoriasis Management by Blue Light Irradiation. Félix Garza ZC, Liebmann J, Born M, Hilbers PA, van Riel NA. Front Physiol 2017; 8: 28 Abstract: Clinical investigations prove that blue light irradiation reduces the severity of psoriasis vulgaris. Nevertheless, the mechanisms involved in the management of this condition remain poorly defined. Despite the encouraging results of the clinical studies, no clear guidelines are specified in the literature for the irradiation scheme regime of blue light-based therapy for psoriasis. We investigated the underlying mechanism of blue light irradiation of psoriatic skin, and tested the hypothesis that regulation of proliferation is a key process. We implemented a mechanistic model of cellular epidermal dynamics to analyze whether a temporary decrease of keratinocytes hyper-proliferation can explain the outcome of phototherapy with blue light. Our results suggest that the main effect of blue light on keratinocytes impacts the proliferative cells. They show that the decrease in the keratinocytes proliferative capacity is sufficient to induce a transient decrease in the severity of psoriasis. To study the impact of the therapeutic regime on the efficacy of psoriasis treatment, we performed simulations for different combinations of the treatment parameters, i.e., length of treatment, fluence (also referred to as dose), and intensity. These simulations indicate that high efficacy is achieved by regimes with long duration and high fluence levels, regardless of the chosen intensity. Our modeling approach constitutes a framework for testing diverse hypotheses on the underlying mechanism of blue light-based phototherapy, and for designing effective strategies for the treatment of psoriasis. This model is hosted on BioModels Database and identified by: BIOMD0000000695. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Circulating Monocytes are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast

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