Ignite Creation Date:
2024-05-06 @ 9:04 AM
Last Modification Date:
2024-10-26 @ 12:09 PM
Study NCT ID:
NCT02891213
Status:
UNKNOWN
Last Update Posted:
2016-09-23
First Post:
2016-09-01
Brief Title:
Study of the Role of Soluble Forms of RAGE sRAGEesRAGE as Diagnostic and Prognostic Biomarkers of Systemic Lupus Erythematosus
Sponsor:
CHU de Reims
Organization:
CHU de Reims
Study Overview
Official Title:
Study of the Role of Soluble Forms of RAGE sRAGEesRAGE as Diagnostic and Prognostic Biomarkers of Systemic Lupus Erythematosus
Status:
UNKNOWN
Status Verified Date:
2016-09
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
R-PA14098
Brief Summary:
Systemic Lupus Erythematosus SLE is the most common systemic autoimmune disease The clinical manifestations are severe and affect multiple target organs such as the kidney central nervous system skin heart and joints Despite the progress made in the therapeutic approach with new immunosuppressive regimens morbi-mortality is still high Therefore its important to identify new biomarkers to help clinicians to predict severity and evolution of the disease for better adaptation of treatments and try to improve the prognosis
RAGE Receptor for Advanced Glycation Endproducts
RAGE Receptor for Advanced Glycation Endproducts is an ubiquitous membrane receptor involved in development of many diseases such as diabetes chronic renal failure but also in vascular remodelling inflammatory infectious deseases and cancer RAGE regulates a number of crucial cell processes like inflammation and tissue and cellular homeostasis
RAGE is able to bind not only the advanced glycation end products AGEs such as pentosidine carboxymethyllysine CML methyl-glyoxal-hydroimidazolone-1 MG- H1 but also other ligands such as HMGB1 high mobility group box1 and S100A8A9 proteins which have been correlated in recent studies to the activity index of SLE The activation of RAGE leads to a cascade of intracellular signaling and activation of the transcription factor NF-ΚB NF-ΚB enable the traduction of proinflammatory cytokines such as IL-6 IL-1α IFN-γ In SLE these cytokines involved in perpetuation of inflammation and tissue damages including lupus nephritis Moreover the activation of RAGE induces the expression of adhesion molecule such as sICAM -1 and sVCAM -1 wich were recently involved in SLE vasculitis
Soluble forms of RAGE sRAGE and esRAGE
RAGE is a proinflammatory membrane receptor But RAGE also exists in soluble plasma forms esRAGE secreted form and sRAGE a truncated form as cleaved by MMP9 and ADAM10 enzymes esRAGE and sRAGE have the same ligand-binding specificity as RAGE and may function as a decoy receptor by binding pro-inflammatory ligands and preventing them from accessing cell surface RAGE Kierdorf and Fritz 2013 Therefore both soluble forms have an anti-inflammatory action Several studies have shown a decrease in circulating levels of sRAGE in patients with Rheumatoid Arthritis or Sjögren Syndrome compared with healthy controls However the role of RAGE in SLE remains unknown
RAGE and Systemic Lupus Erythematosus recent advances
Our team Laboratory of Nephrology CNRS UMR 7369 URCA showed in a study in lupus RAGE knockout mice B6 MRL-FAS lprJ RAGE-- a strong involvement of RAGE in systemic manifestations SLE Recently another report showed that sRAGE has an anti-inflammatory effect on the lupus nephritis and could be a potent therapy in mice
In humans two studies show a correlation between the plasma level of sRAGE and lupus phenotype Nienhuis et al 2008
Working hypothesis
Based on the results and those of the current studies the investigators think that RAGE axis and its soluble forms play a crucial role in the complex pathogenesis of SLE
The investigators hypothesize that plasma levels sRAGE and esRAGE are a reflection of the activity and the development of SLE in humans Soluble forms of RAGE and ligands may be novel biomarkers of SLE and sRAGE a potent therapeutic target
RAGE Receptor for Advanced Glycation Endproducts
RAGE Receptor for Advanced Glycation Endproducts is an ubiquitous membrane receptor involved in development of many diseases such as diabetes chronic renal failure but also in vascular remodelling inflammatory infectious deseases and cancer RAGE regulates a number of crucial cell processes like inflammation and tissue and cellular homeostasis
RAGE is able to bind not only the advanced glycation end products AGEs such as pentosidine carboxymethyllysine CML methyl-glyoxal-hydroimidazolone-1 MG- H1 but also other ligands such as HMGB1 high mobility group box1 and S100A8A9 proteins which have been correlated in recent studies to the activity index of SLE The activation of RAGE leads to a cascade of intracellular signaling and activation of the transcription factor NF-ΚB NF-ΚB enable the traduction of proinflammatory cytokines such as IL-6 IL-1α IFN-γ In SLE these cytokines involved in perpetuation of inflammation and tissue damages including lupus nephritis Moreover the activation of RAGE induces the expression of adhesion molecule such as sICAM -1 and sVCAM -1 wich were recently involved in SLE vasculitis
Soluble forms of RAGE sRAGE and esRAGE
RAGE is a proinflammatory membrane receptor But RAGE also exists in soluble plasma forms esRAGE secreted form and sRAGE a truncated form as cleaved by MMP9 and ADAM10 enzymes esRAGE and sRAGE have the same ligand-binding specificity as RAGE and may function as a decoy receptor by binding pro-inflammatory ligands and preventing them from accessing cell surface RAGE Kierdorf and Fritz 2013 Therefore both soluble forms have an anti-inflammatory action Several studies have shown a decrease in circulating levels of sRAGE in patients with Rheumatoid Arthritis or Sjögren Syndrome compared with healthy controls However the role of RAGE in SLE remains unknown
RAGE and Systemic Lupus Erythematosus recent advances
Our team Laboratory of Nephrology CNRS UMR 7369 URCA showed in a study in lupus RAGE knockout mice B6 MRL-FAS lprJ RAGE-- a strong involvement of RAGE in systemic manifestations SLE Recently another report showed that sRAGE has an anti-inflammatory effect on the lupus nephritis and could be a potent therapy in mice
In humans two studies show a correlation between the plasma level of sRAGE and lupus phenotype Nienhuis et al 2008
Working hypothesis
Based on the results and those of the current studies the investigators think that RAGE axis and its soluble forms play a crucial role in the complex pathogenesis of SLE
The investigators hypothesize that plasma levels sRAGE and esRAGE are a reflection of the activity and the development of SLE in humans Soluble forms of RAGE and ligands may be novel biomarkers of SLE and sRAGE a potent therapeutic target
Detailed Description:
Expected results
The investigators expect a correlation between serum sRAGE esRAGE and activity of SLE and the presence of visceral involvement Furthermore this study will allow us to analyze for the first time in a lupus population the correlation between soluble forms of RAGE esRAGE sRAGE and cytokines and molecules involved in lupus visceral involvement as IL-6 IL-1α IFN-γ sICAM-1 and sVCAM-1
Completion of our project will allow better understanding of the role of RAGE and RAGE ligand in SLE activity and will provide rationale for prospective study
Future perspectives will include assessment of the risk-benefit for the use of anti-RAGE strategies or recombinant sRAGEesRAGE molecules as adjuvant treatment for SLE
Study Design the investigators designed an retrospective analytic transversal mulitcentric study the investigators would like to use the serum and the clinical information collected in Lupus BioBanque du Rhin Supérieur LBBR UF 9882 to measure soluble forms of RAGE RAGE-ligands cytokines and sICAM and sVCAM The investigators would like to include 150 patients in this study
Aim 1 The main objective of this study is to investigate the association between Systemic Lupus Erythematosus SLE activity as measured by the SLEDAI score and serum concentrations of sRAGE and esRAGE
Aim 2 The study of the correlation between the activity of other activity markers of SLE and soluble forms of RAGE
1 the concentration of RAGE ligands AGEs like CML pentosidine and MG-H1 and soluble forms of RAGE esRAGE sRAGE
2 the cytokine profile IL-6 IL-1α IFN-γ and soluble forms of RAGE esRAGE sRAGE
3 The concentrations of sICAM-1 and sVCAM-1 and soluble forms of RAGE esRAGE sRAGE
Methods
Inclusion criteria are
the LBBR inclusion criteria
and Absence of immunomodulatory treatment
and preserved renal function MDRD 60mlmin
Exclusion criteria are
renal failure defined by MDRD clearance 60 mLminm2
or neoplasia
or diabetes
or other autoimmune disease
or current immunosuppressive treatments
Data collection About 500 μl of serum will be necessary for each patients to make all measurements
Mass spectrometry will be used for measurement of RAGE ligands Advanced glycation end products such as CML pentosidine and MG-H1
Commercially available ELISA kits will be used for measurement of sRAGE esRAGE sVCAM1
Flow Cytometry will be used for measurement of cytokines IL-6 IL-1a IFN-y and sICAM1
The investigators expect a correlation between serum sRAGE esRAGE and activity of SLE and the presence of visceral involvement Furthermore this study will allow us to analyze for the first time in a lupus population the correlation between soluble forms of RAGE esRAGE sRAGE and cytokines and molecules involved in lupus visceral involvement as IL-6 IL-1α IFN-γ sICAM-1 and sVCAM-1
Completion of our project will allow better understanding of the role of RAGE and RAGE ligand in SLE activity and will provide rationale for prospective study
Future perspectives will include assessment of the risk-benefit for the use of anti-RAGE strategies or recombinant sRAGEesRAGE molecules as adjuvant treatment for SLE
Study Design the investigators designed an retrospective analytic transversal mulitcentric study the investigators would like to use the serum and the clinical information collected in Lupus BioBanque du Rhin Supérieur LBBR UF 9882 to measure soluble forms of RAGE RAGE-ligands cytokines and sICAM and sVCAM The investigators would like to include 150 patients in this study
Aim 1 The main objective of this study is to investigate the association between Systemic Lupus Erythematosus SLE activity as measured by the SLEDAI score and serum concentrations of sRAGE and esRAGE
Aim 2 The study of the correlation between the activity of other activity markers of SLE and soluble forms of RAGE
1 the concentration of RAGE ligands AGEs like CML pentosidine and MG-H1 and soluble forms of RAGE esRAGE sRAGE
2 the cytokine profile IL-6 IL-1α IFN-γ and soluble forms of RAGE esRAGE sRAGE
3 The concentrations of sICAM-1 and sVCAM-1 and soluble forms of RAGE esRAGE sRAGE
Methods
Inclusion criteria are
the LBBR inclusion criteria
and Absence of immunomodulatory treatment
and preserved renal function MDRD 60mlmin
Exclusion criteria are
renal failure defined by MDRD clearance 60 mLminm2
or neoplasia
or diabetes
or other autoimmune disease
or current immunosuppressive treatments
Data collection About 500 μl of serum will be necessary for each patients to make all measurements
Mass spectrometry will be used for measurement of RAGE ligands Advanced glycation end products such as CML pentosidine and MG-H1
Commercially available ELISA kits will be used for measurement of sRAGE esRAGE sVCAM1
Flow Cytometry will be used for measurement of cytokines IL-6 IL-1a IFN-y and sICAM1
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None