Molecular Reclassification to Find Clinically Useful Biomarkers for Systemic Autoimmune Diseases:

Completed

• Conditions: Systemic Autoimmune Diseases

• Registration Number: NCT02890121
• Lead Sponsor: Fundación Pública Andaluza Progreso y Salud

Brief Summary

Connective tissue diseases (CTD) or systemic autoimmune diseases (SADs) as they are known today are a group of chronic inflammatory conditions with autoimmune aetiology with few treatment options and difficult diagnosis.Brest team contribute to perform a new classification of the following systemic autoimmune diseases in a European Union's Seventh Framework Programme. The aim of this research is to reclassify the individuals affected by SADs into molecular clusters instead of clinical entities through the determination of molecular profiles using several "Omics" techniques.

Detailed Description

The main objective of the PRECISESADS project is to reclassify the individuals affected by SADs into molecular clusters instead of clinical entities through the determination of molecular profiles using several "-omics" techniques.

The specific objectives of this cross sectional study and sub-study are:

1. To identify a systemic taxonomy for patients with SADs by producing the following data in individuals with SADs and controls: genetic, epigenomic, transcriptomic, flow cytometric (from peripheral blood mononuclear and polymorphonuclear cells (PBMCs)), metabolomics and proteomic in plasma and urine, exosome analysis, classical serology (antibodies and autoantibodies), and clinical data.

2. To better characterize individual SADs at the omics level.

3. To perform clustering analyses to determine the groups of individuals who, differentially from other groups, share specific molecular features (precision medicine).

4. To identify gene expression, methylation profiles through deconvolution methods comparing a mixture of cells with subpopulations determined by flow cytometry with separated cells, cytokine profiles and plasma metabolomics using Mass Spectrometry, in a substudy of 288 individuals.

The clustering process will be data-driven with the aim to find the most homogenous and differentiated clusters of diseases that clearly separate individuals on the basis of, serological, genetic, epigenomic, cellular (cell proportions), metabolomic, proteomic (cytokines, autoantibodies) and transcriptome characteristics and differentiate them from controls and other patient clusters.

A total of 2000 patients and 666 controls will be included in the study, adjusted to the following distribution:

* A total of 400 patients diagnosed with systemic lupus erythematosus (SLE)

* A total of 400 patients diagnosed with rheumatoid arthritis (RA)

* A total of 400 patients diagnosed of scleroderma or systemic sclerosis (SSc)

* A total of 400 patients diagnosed of Sjögren's syndrome (SjS)

* A total of 400 patients diagnosed of primary antiphospholipid syndrome (PAPS) or Mixed Connective Tissue Disease (MCTD) or with undifferentiated disease • All patients will be recruited from 18 sites in Europe (Austria, Belgium, France, Germany, Italy, Portugal, Spain, Hungary and Switzerland).

Study Timeline

• Study Start: 2014-12
• Study First Submitted: 2016-08-22
• Study First Submitted QC: 2016-08-31
• Study First Posted: 2016-09-07
• Primary Completion: 2017-10
• Study Completion: 2017-10
• Status Verified: 2018-04
• Last Update Submitted: 2018-05-22
• Last Update Posted: 2018-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 2006

Inclusion Criteria

• · Aged 18 years or older at the time of consent

  • Diagnosed according to prevailing criteria for one of the following systemic autoimmune diseases (see Annex 2)

    • Rheumatoid arthritis (RA)
    • Scleroderma or systemic sclerosis (SSc)
    • Primary Sjögren's syndrome (SjS)
    • Systemic lupus erythematosus (SLE)
    • Primary antiphospholipid syndrome (PAPS)
    • Mixed Connective Tissue Disease (MCTD)
    • Patients with undifferentiated connective tissue disease (UCTD) for over 1 year and that do not fulfill the diagnosis of any of the above diseases.

  • Signed the informed consent form

Exclusion Criteria

• · Patients unable to understand the procedures related to the protocol should not be included. The study is voluntary and patients must be able to give their informed consent.

  • Pregnant women

  • Neonatal lupus

  • Drug-induced lupus

  • Patients whose condition is so serious that they cannot take part in the study

  • Severe nephrotic syndrome with proteinuria >=3,5 g/day

  • Patients with stable doses of steroids >15mg/day for the last 3 months or with IV corticosteroids in the last 3 months

  • Patients under immunosuppressants for the last 3 months prior to recruitment with:

    • Methotrexate ≥25mg/week
    • Azathioprine ≥2.5mg/kg/day
    • Cyclosporine A > 3mg/kg/day
    • Mycophenolate Mofetil > 2gr/day

  • Treatment with cyclophosphamide (any dose or route of administration) or Belimumab in the past 6 months

  • Patients with combined therapy of two or more immunosuppressants

  • Patients on depletive therapy such as Rituximab in the last year

  • Patients receiving experimental therapy.

  • Chronic HBV or HCV infection

  • Overlap syndromes

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Gene expression in total blood	2 years	Gene expression will be done using commercial gene expression microarrays in total blood from all samples using the RNA Paxgene tube.
Flow cytometry analysis to determine cell proportions in the total blood mixture in all individuals.	24 hours	9 optimized panels of antibodies will be used to determine cell subpopulations in peripheral blood (including very minor cell populations).
Metabolite determination	2 years	Metabolite determination in plasma and urine using Nuclear Magnetic Resonance
Genotyping	2 years	Genotyping will be done using a whole genome array
Exosome isolation from plasma and urine	2 years	set up of the methodology for isolating exosomes in these bodily fluids for gene expression analysis
routine autoantibodies in serum	2 years	set of serum autoantibodies will be determined in a European validated laboratory. Also, they will perform detection of antibodies against small lipid moieties i.e.antiphosphorylcholine), lupus anticoagulant and complement proteins in plasma.
Cytokine profile determination	2 years	88 different cytokines will be assessed with Luminex
Gene methylation in total blood	2 years	Methylation analysis will be done using the methylome 450k array using the DNA obtained from total blood. MicroRNA gene expression arrays using total blood.

Trial Locations

Locations (18)

Université catholique de Louvain - Cliniques Universitaires Saint-Luc; 🇧🇪 Brussels, Belgium

Medical University of Vienna; 🇦🇹 Vienna, Austria

Deutsches Rheuma-Forschungszentrum Berlin (DRFZ); 🇩🇪 Berlin, Germany

UZ Leuven - KU Leuven, Department of Rheumatology (KU LEUVEN); 🇧🇪 Leuven, Belgium

CHRU de Brest; 🇫🇷 Brest, France

University of Cologne; 🇩🇪 Cologne, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

University of Szeged; 🇭🇺 Szeged, Hungary

UNIMI, Istituto Ortopedico Getano Pini; 🇮🇹 Milan, Italy

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico (IRCCS); 🇮🇹 Milan, Italy

Hospital Universitario Reina Sofía Andaluz de Salud; 🇪🇸 Cordoba, Spain

Hospital Virgen de las Nieves Granada; 🇪🇸 Granada, Spain

Centro Hospitalar do Porto; 🇵🇹 Porto, Portugal

Hospital Clinic I Provicia- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); 🇪🇸 Barcelona, Spain

Hospital Universitario San Cecilio Servicio Andaluz de Salud; 🇪🇸 Granada, Spain

Hospital Regional de Málaga Servicio Andaluz de Salud; 🇪🇸 Malaga, Spain

Hospital Universitario Marqués de Valdecilla, Servicio Cántabro de Salud; 🇪🇸 Santander, Spain

Hospitaux Universitaires de Géneve; 🇨🇭 Geneve, Switzerland