Genomic Effects of Glucocorticoids in Patients With Systemic Lupus Erythematosus

Early Phase 1

Completed

Conditions: Systemic Lupus Erythematous (SLE)

Interventions: Drug: Solu-Medrol 1mg/kg
Drug: Solu-Medrol 250 mg

Registration Number: NCT04233164

Lead Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Brief Summary: Background:

The immune system is the body's defense against bacteria and other harmful invaders. In people with systemic lupus erythematosus (SLE), the immune system becomes overactive and attacks healthy cells by mistake. Many people use glucocorticoids (GCs) to treat their SLE. GCs can calm down an overactive immune system by changing how the body reads genes. But GCs have side effects that can increase over time. Researchers want to learn more about how GCs work. This may help to develop new and better drugs for treating SLE without the side effects GCs have.

Objective:

To better understand how GCs affect the immune system in people with SLE.

Eligibility:

People age 18-80 with SLE.

Design:

Participants will be screened with a physical exam. They will have a health and medical history. They will have blood and urine tests. They will have an electrocardiogram to measure heart activity. For this, sticky pads are put on their chest, arms, and legs.

Participants will have a methylprednisolone infusion for about 30 minutes. It will be given through a needle in a vein.

Blood will be collected immediately before, 2 hours after, and 4 hours after the start of the infusion. Blood pressure and heart activity will be monitored. Participants will repeat some of the screening tests.

Participants will be contacted twice in the week after the infusion visit. They will discuss any health problems they are having.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A: Glucocorticoids 1 mg/kg dose	Solu-Medrol 1mg/kg	Participants with Systemic Lupus Erythematosus (SLE) received a single intravenous dose of methylprednisolone 1 mg/kg and blood was collected two hours and four hours after the start of the infusion.
Group B: Glucocorticoids 250 mg dose	Solu-Medrol 250 mg	Participants with Systemic Lupus Erythematosus (SLE) received a single intravenous dose of 250 mg of methylprednisolone and blood was collected two hours and four hours after the start of the infusion.

Primary Outcome Measures

Name	Time	Method
Number of SLE Patients That Were Sampled for RNA-seq Differential Expression Analysis (Biological Replicates)	2 hours and 4 hours post infusion	Number of of SLE patients that were sampled for RNA-seq differential gene expression analysis in glucocorticoid-treated immune cells. The analysis employed a cutoff value of \< 5% false-discovery rate (FDR) to select the transcripts that were considered differentially expressed at each time point. The resulting gene lists were contrasted to determine which genes were uniquely differentially expressed in different cell types.

Secondary Outcome Measures