Neutrophil Extracellular Traps in Different Forms of Systemic Sclerosis (NETOSE)

Neutrophil Extracellular Traps in Systemic Sclerosis

Systemic SClerosis (SSC) is a systemic disease characterized by limited or diffuse cutaneous sclerosis, microangiopathy, overproduction of autoantibodies and variable organ damage due to vasculopathy and/or fibrosis. The loss of self-tolerance is believed to be caused by the dysregulation of both innate and adaptive immune systems and may involve Reactive Oxygen Species (ROS).

Neutrophils are potent producers of ROS and may play a role in endothelial cells and fibrobasts dysfunction, as in autoantibodies generation. However, their role in SSC pathogenesis remains to be determined. Recent studies discovered abnormal regulation of Neutrophil Extracellular Traps (NETs) in other auto-immune diseases such as Systemic Lupus Erythematosus (SLE). NETs are web-like structures composed of chromatin backbones and granular molecules. They are released by activated neutrophils through a process called "NETosis". Nets were first described in 2004 as a novel host defense mechanism to trap and kill foreign pathogens. Recent evidence shows that NETs also participate in the pathogenesis of a variety of inflammatory and autoimmune diseases, including SLE.

The investigators recently highlighted this phenomenon in SSc, especially in patients with vascular complications and/or at a early stage of the disease. The investigators will now explore the factors implicated in this dysregulation of NETosis in SSc.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus; Systemic Sclerosis; Dermatomyositis; ANCA Associated Vasculitis; Other Connective Tissue Disease
• Intervention / Treatment: Other: Blood sample

Detailed Description

This study is designed to assess the role of Neutrophil Extracellular Traps (NETs) in Systemic SClerosis (SSC) as well as to evaluate the correlation between NETs production and NETs composition and the different complications and phenotypes observed in SSC.

100 SSC patients, 30 other connective tissue disease patients and 130 healthy subjects will be recruited. Blood samples will be collected to obtain plasma, serum and polynuclear neutrophils by negative selection.

• Study Type: Observational
• Enrollment (Estimated): 260

Contacts and Locations

• Study Contact: Name: Kevin DIDIER, Dr.; Phone Number: 03.26.83.24.44; Email: kdidier@chu-reims.fr

Study Locations

• France
  • Reims, France, 51092
    • Recruiting
    • Chu Reims
    • Contact: Damien JOLLY, Pr.; Phone Number: 33 326788472; Email: djolly@chu-reims.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Group 1 : Adult with SSc Group 2 : Adult with other connective tissue disease Group 3 : Healthy adult volunteer

Description

Inclusion Criteria:

*For patients of group 1:

• Patients with systemic sclerosis (ACR-EULAR Criteria)
• Patients taking care of in internal medicine or in dermatology department's of the university hospital of Reims
• Patients consenting to participate to the study
• Patients enrolled in the national healthcare insurance program

For patients of group 2:

• Patients with other connective tissue disease (ACR specific-disease criteria)
• Patients taking care of in internal medicine or in dermatology department's of the university hospital of Reims
• Patients consenting to participate to the study
• Patients enrolled in the national healthcare insurance program

For patients of group 3 (healthy volunteers)

• Patients eligible for blood donation (blood donation regulation criteria of January 11th 2022 decree)
• Patients without medical history of autoimmune systemic or chronic inflammatory systemic disease,
• Patients without current or past neoplasy disease,
• Patients without chronic metabolic pathology
• Patients without treatment by anti inflammatory or corticotherapy for the last 15 days,
• Patients without infectious pathology or inflammatory acute for the last 15 days
• Patients consenting to participate to the study

Exclusion Criteria for patients of all groups:

• Patients/Healthy volunteers under 18 years old
• Patients/Healthy volunteers protected by the law
• Patients/Healthy volunteers not consenting to participate to the study after information
• Patients with inflammatory pathology or infectious acute intercurrent pathology in the last 15 days before inclusion
• Pregnant or breastfeeding women

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adult with SSc	Other: Blood sample; Blood sample to quantify and qualify NETosis in vivo and ex vivo after different stimulations.
Other connective tissue disease; Adult with other connective tissue disease	Other: Blood sample; Blood sample to quantify and qualify NETosis in vivo and ex vivo after different stimulations.
Control; Healthy adult volunteer	Other: Blood sample; Blood sample to quantify and qualify NETosis in vivo and ex vivo after different stimulations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of Neutrophil Extracellular Traps (NETs) generated after stimulation of neutrophils in vitro by serum from SSC, SLE and healthy controls.	Comparative analysis of the quantity of Neutrophil Extracellular Traps (NETs) generated after stimulation of neutrophils in vitro by serum from SSC, other connective tissue diseases and healthy controls. Neutrophils from SSC, other connective tissue diseases and healthy subjects will be used.	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of the composition of Neutrophil Extracellular Traps (NETs)	Comparative analysis of the composition of Neutrophil Extracellular Traps (NETs) generated after stimulation of neutrophils in vitro by serum from SSC, other connective tissue diseases and healthy controls. Neutrophils from SSC, other connective tissue diseases and healthy subjects will be used.	Day 0
Analysis of the cytokines influencing Neutrophil Extracellular Traps NETs production in vitro	Comparative analysis of the quantity of Neutrophil Extracellular Traps (NETs) generated after stimulation of neutrophils from SSC patients in vitro by differents cytokines	Day 0

Collaborators and Investigators

• Sponsor: CHU de Reims

Publications and helpful links

General Publications

• Didier K, Giusti D, Le Jan S, Terryn C, Muller C, Pham BN, Le Naour R, Antonicelli FD, Servettaz A. Neutrophil Extracellular Traps Generation Relates with Early Stage and Vascular Complications in Systemic Sclerosis. J Clin Med. 2020 Jul 7;9(7):2136. doi: 10.3390/jcm9072136.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2023
• Primary Completion (Estimated): October 27, 2028
• Study Completion (Estimated): April 27, 2029

Study Registration Dates

• First Submitted: June 12, 2024
• First Submitted That Met QC Criteria: June 12, 2024
• First Posted (Actual): June 17, 2024

Study Record Updates

• Last Update Posted (Actual): June 17, 2024
• Last Update Submitted That Met QC Criteria: June 12, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Systemic sclerosis; NETosis; polymorphonuclear neutrophil
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Skin Diseases, Vascular; Polymyositis; Myositis; Systemic Vasculitis; Sclerosis; Lupus Erythematosus, Systemic; Scleroderma, Systemic; Scleroderma, Diffuse; Connective Tissue Diseases; Dermatomyositis; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Other Study ID Numbers: PO23126

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No