Transcriptional and Immine Parameters of Response to Belinumab
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|ClinicalTrials.gov Identifier: NCT04570306|
Recruitment Status : Not yet recruiting
First Posted : September 30, 2020
Last Update Posted : December 7, 2020
|Condition or disease||Intervention/treatment|
|Systemic Lupus Erythematosus||Drug: Belimumab|
B-cell activating factor (BAFF) excess causes lupus disease by exerting costimulatory effects on the B-cell compartment but also on a variety of non-B-cell subsets such as T-helper cells and monocytes/dendritic cells. The 2019 updated European League Against Rheumatism (EULAR) recommendations for SLE recommend usage of belimumab (anti-BAFF mAb) in persistently active or flaring disease based upon evidence for efficacy, reduction of flares and organ damage accrual without increasing the risk of infections. Still, belimumab is usually reserved for established, refractory cases. It is conceivable that earlier usage may halt the progression of the disease, especially prevent flares and dysfunction in major organs. The investigators have completed a combined genetic and transcriptomic analysis in the peripheral blood of SLE patients and have characterized distinct gene signatures for disease activity/flare and severity. Using machine learning techniques, the investigators can predict SLE patients likely to develop major organ involvement. In vitro and gene profiling studies in purified lupus monocytes indicate that these cells exist - under the effect of type I interferon - in a "high alert" autoreactive and metabolic state (reminiscent of 'trained immunity'), which may contribute to risk of flares, tissue injury but also major comorbidities seen in SLE, particularly accelerated atherosclerosis and infections. Based upon the clinical experience accumulated thus far, it is likely that belimumab may neutralize these molecular signatures for flares and disease progression without interfering with host defense immune pathways.
The investigators propose to perform RNA-sequencing of the whole blood initially, in a cohort of 80 SLE patients who will receive belimumab as part of standard clinical practice, in order to assess intra-patient longitudinal (baseline, 1, 3 and 6 months) transcriptome changes and examine whether treatment can ameliorate the identified activity/flare, severity and major organ disease signatures. The investigators will also obtain preliminary information on molecular signatures predicting clinical responses and the impact of belimumab on gene signatures of host defense against viral and bacterial (including mycobacterial) pathogens. Using modules of cell type-specific genes and co-expression gene networks, the investigators will deconvolute our data to define pertinent molecular alterations in specific immune cell types. Results will be validated and functionally characterized by single-cell mass cytometry (performed at the aforementioned time points), which enables investigation of the cell identity (including subsets of B-cells and myeloid cells of particular relevance to the disease) and activation status at protein level (e.g. phosphorylation) through next-generation, high-dimensional flow cytometry. Through a focused analysis of the deconvoluted RNA-seq and mass cytometry data followed by targeted gene expression and function studies in purified monocytes, the investigators will determine whether belimumab can restore "SLE-primed" monocytes thus, alleviating their inflammatory and pro-atherogenic phenotype and enhancing their bactericidal activity. Collectively, these studies will provide novel mechanistic insights on the beneficial efficacy/toxicity ratio of belimumab therapy in SLE, while supporting the early use of the drug.
|Study Type :||Observational|
|Estimated Enrollment :||80 participants|
|Official Title:||Whole Blood Transcriptional and Mass Cytometry Immune Profiling in Systemic Lupus Erythematosus (SLE) Patients to Discern the Salutary Effects of Belimumab on Halting Disease Progression and Flares Without Compromising Host Fitness|
|Estimated Study Start Date :||December 31, 2020|
|Estimated Primary Completion Date :||December 30, 2023|
|Estimated Study Completion Date :||December 30, 2023|
Belimumab-treated SLE patients
SLE patients with active disease who will be started on add-on treatment with belimumab on top of standard of care.
The study will involve 80 adult patients diagnosed with SLE who will be started on belimumab (standard approved dose of i.v. 10 mg/kg or subcutaneous 200 mg/week) due to active disease. The intention to start belimumab will be made by the treating Rheumatologist(s), in accordance to the current standard of care, and on the basis of shared physician-patient decision making.
- Changes in blood transcriptome in relation to clinical response induced by belimumab [ Time Frame: 1, 3 and 6 months ]To evaluate changes in SLE blood transcriptome that are induced by treatment with belimumab with emphasis on the reversibility of previously-defined gene signatures for disease activity/flare, severity/progression and major organ involvement. Results will be correlated with validated patient outcomes such as clinical response (defined according to SLE Responder Index-4).
- Changes in blood transcriptome in relation to low disease activity induced by belimumab [ Time Frame: 3 and 6 months ]To evaluate changes in SLE blood transcriptome that are induced by treatment with belimumab with emphasis on the reversibility of previously-defined gene signatures for disease activity/flare, severity/progression and major organ involvement. Results will be correlated with low disease activity in SLE (according to the Low Disease Activity State definition)
- Changes in blood transcriptome in relation to remission induced by belimumab [ Time Frame: 6 months ]To evaluate changes in SLE blood transcriptome that are induced by treatment with belimumab with emphasis on the reversibility of previously-defined gene signatures for disease activity/flare, severity/progression and major organ involvement. Results will be correlated with remission in SLE (according to the Definition of Remission [DORIS] in SLE)
Biospecimen Retention: Samples With DNA
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04570306
|Contact: Dimitrios T BOUMPAS, MDemail@example.com|
|Study Chair:||Dimitrios T Boumpas, MD||Biomedical Research Foundation, Academy of Athens|