Expression kinetics of glucocorticoid receptor isoforms predicts treatment response to glucocorticoids in uveitis patients

Abstract

Purpose: Glucocorticoids (GC) have been the mainstay therapy for autoimmue uveitis for decades, but up to one third of patients are unable to achieve disease control at tolerable GC doses, developing vision-threatening complications and requiring immunosuppressive therapy (IMT). Glucocorticoid receptor (GR)-isoforms - including two classical post-transcriptional GR alpha isoform (GRα) and beta isoform (GRβ)- have been implicated in the mechanism of GC resistance. However, the utility of using GR isoforms in uveitis patients, to identify GC resistance, have not been fully investigated. In this study, we evaluate the expression kinetics of GRα and GRβ in peripheral blood mononuclear cells (PBMCs) in uveitis patients, and test whether it can be used to identify GC resistance at an early point.

Methods: Twenty-one systemic treatment naïve autoimmune uveitis patients were recruited. GC resistance was defined as a persistence of active intraocular inflammation, despite of treatment with 1 mg /kg/day of oral prednisone for at least one month. Otherwise, patients were categorized as GC-sensitive. Real-Time qPCR were performed to measure mRNA levels of GR α/β in PBMCs, at baseline and two weeks after prednisone initiation.

Results: There is no significant difference on the expression levels of GRα and GRβ between GC-sensitive and GC-resistant patients at baseline. After two weeks of prednisone treatment, the expression of GRα increased in GC-sensitive patients, while there was a decrease of this isoform in GC-resistant patients (5.5 fold vs 0.7 fold, p=0.01). GRβ expression increased in both groups with a significant higher level in GC-sensitive patients (6.6 fold vs 4.6 fold, p=0.03). The expression levels of GR isoforms were independent of disease activity.

Conclusions: The evaluation of expression kinetics of GR isoforms could potentially serve as a biomarker to early identify GC-resistant uveitis patients. These results contribute to our knowledge in understanding the complex mechanism of GR resistance and may facilitate clinical decision-making in the management of autoimmune uveitis.