Cristhian A Urzua1, Ping Chen2, Benjamin Chaigne-Delalande2, Baoying Liu2, Rodrigo Anguita3, Julia Guerrero3, Pablo Sabat3, Victor Velasquez3, H Nida Sen2, Richard W J Lee4, Annelise Goecke3. 1. Department of Ophthalmology, Faculty of Medicine, University of Chile, Santiago, Chile; Facultad de Medicina, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile; Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: cristhian.urzua@uchile.cl. 2. Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. 3. Department of Ophthalmology, Faculty of Medicine, University of Chile, Santiago, Chile. 4. Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom; Moorfields Eye Hospital National Health Service Foundation Trust, London, United Kingdom.
Abstract
PURPOSE: To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Prospective cohort study. METHODS: Twenty VKH patients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (β) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex). RESULTS: After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKH patients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005). CONCLUSIONS: In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients' clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.
PURPOSE: To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Prospective cohort study. METHODS: Twenty VKHpatients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (β) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex). RESULTS: After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKHpatients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005). CONCLUSIONS: In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients' clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.