Expression Dynamics Of Cytokine Genes Is Related To The Apremilast Treatment Effectiveness In Patients With Severe Psoriasis

Abstract

Background — Psoriasis is an immune-mediated genetic skin disease with a deregulated immune response governed by a proinflammatory cytokine network. Apremilast has demonstrated high safety and tolerability both in clinical trials and in clinical practice. The effectiveness of the apremilast use in clinical practice may differ from major clinical trials. Our study assessed changes in the levels of immune gene expression in patients suffering from severe psoriasis in the course of apremilast treatment in order to investigate the predictors of its effectiveness. Methods — We assessed the expression levels of IFNγ, IRF3, GLIS1, HR, STAT1, STAT3, VEGFA, ICAM1, TNF, IL1α, IL1β, IL4, IL6, IL10, IL11, IL12B, IL17A, IL17F, IL18, IL20, IL21, IL22, IL23A, IL25, IL31, IL33 genes in both lesional and nonlesional skin before the treatment, as well the expression at lesional skin after the treatment. RNA expression was assessed in skin biopsy samples by RT-PCR using TaqMan probes with StepOne5 equipment and normalized with endogenous control. The study included 16 patients diagnosed with a moderate-to-severe or severe psoriasis using clinical examination by a dermatologist. The clinical outcome after 26 weeks of apremilast treatment was assessed with delta PASI, resulting in a patient group with high effectiveness of treatment (delta PASI>75%) and a group including all other patients. Results — We confirmed elevated levels of expression in STAT1, IFNγ, IL1β, IL12B, IL17A, IL17F, IL20, IL21, IL22, and IL23A genes in lesional vs. nonlesional psoriatic skin samples, while GLIS1 gene expression was reduced. The expression levels of cytokine genes after apremilast treatment decreased considerably in cytokines IFNγ, IL1β, IL20, IL21, and IL22; and to a lesser extent in STAT1, IL6, IL17F, IL22 and IL31. In the group of those who effectively responded to treatment with apremilast, a five-to-eleven-fold reduction in the expression level of the IL1B, IL6, and IL17F genes was observed, as compared with other patients. Conclusion — The increased expression of cytokine genes in lesional vs. nonlesional skin was reduced after apremilast treatment of psoriasis. We established that fold changes in the expression of the IL1β, IL6 and IL17F genes during treatment with apremilast were different in groups of patients with different therapy outcomes. Hence, we propose that they are the predictors of the effectiveness of apremilast treatment for severe psoriasis.