Genomic Effects of Glucocorticoids in Patients With Systemic Lupus Erythematosus

Study Design: This is a study of the acute effects of glucocorticoids on the immune system of patients with SLE. Participants will undergo baseline blood collection prior to receiving a single intravenous (IV) dose of methylprednisolone sodium succinate. Participants will be randomized into 1 of 2 dose groups: 1 mg/kg or 250 mg. Blood will be collected again at 2 and 4 hours after the methylprednisolone infusion. Individual participation requires 2 visits to the NIH CC and 2 follow-up phone calls. Total length of individual subject participation including screening is 1-12 weeks. Blood samples will be processed for isolation of hematopoietic cell sub-populations (eg, neutrophils, B cells, plasmacytoid dendritic cells, CD4+ T cells, CD8+ T cells, monocytes, and natural killer cells). Laboratory studies will be performed on the purified cells, with the goal of understanding the human response to glucocorticoids in vivo at the level of circulating cell populations (eg, flow cytometry, mass cytometry), RNA (eg, RNA sequencing \[RNA-seq\], small-RNA-seq, real-time polymerase chain reaction \[PCR\]), DNA (eg, chromatin immunoprecipitation sequencing \[ChIP-seq\], methylation analysis, DNA sequencing, genotyping), and protein (eg, flow cytometry, mass spectrometry). At each time point, serum methylprednisolone levels will be measured. Study Agent/ Intervention Description: A single IV infusion of methylprednisolone sodium succinate at either 1 mg/kg or 250 mg. Primary Objective: To understand the cellular and molecular response to glucocorticoids in individuals with SLE. Glucocorticoid Genomics in SLE Secondary Objectives: 1. To identify candidate targets for therapeutic interventions that could mimic the action of glucocorticoids in patients with SLE, without the significant toxicity caused by the broad range of glucocorticoid actions. 2. To test whether the transcriptional response to glucocorticoids differs between the two doses being studied. 3. To identify similarities and differences, at baseline and in response to glucocorticoids, between the transcriptome of cells from patients and those from the previously studied healthy subjects. Primary Endpoint: A list of human protein-coding genes and non-coding RNAs that are differentially expressed in response to glucocorticoids in patients with SLE, for each of the studied cell types and doses. Secondary Endpoints: 1. A comparison of the transcriptional response to glucocorticoids between the two dose groups. 2. A list of protein-coding and non-coding transcripts, their corresponding proteins, and the molecular pathways representing the best candidates for targeted therapeutic alternatives to glucocorticoids. 3. Validation of the targets identified by functional studies. 4. For each cell type, a list of protein-coding or non-coding transcripts that are shared and a list of transcripts that are different, between patients with SLE and the previously studied healthy controls, at baseline or in response to glucocorticoids.