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

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Autoimmune Diseases

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 Type: Observational
• Enrollment (Actual): 2006

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Medical University of Vienna
• Belgium
  • Brussels, Belgium
    • Université catholique de Louvain - Cliniques universitaires Saint-Luc
  • Leuven, Belgium
    • UZ Leuven - KU Leuven, Department of Rheumatology (KU LEUVEN)
• France
  • Brest, France, 29609
    • CHRU de Brest
• Germany
  • Berlin, Germany
    • Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)
  • Cologne, Germany
    • University of Cologne
  • Hannover, Germany
    • Medizinische Hochschule Hannover
• Hungary
  • Szeged, Hungary
    • University of Szeged
• Italy
  • Milan, Italy
    • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico (IRCCS)
  • Milan, Italy
    • UNIMI, Istituto Ortopedico Getano Pini
• Portugal
  • Porto, Portugal
    • Centro Hospitalar do Porto
• Spain
  • Barcelona, Spain
    • Hospital Clinic I Provicia- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
  • Cordoba, Spain
    • Hospital Universitario Reina Sofía Andaluz de Salud
  • Granada, Spain
    • Hospital Universitario San Cecilio Servicio Andaluz de Salud
  • Granada, Spain
    • Hospital Virgen de las Nieves Granada
  • Malaga, Spain
    • Hospital Regional de Málaga Servicio Andaluz de Salud
  • Santander, Spain
    • Hospital Universitario Marqués de Valdecilla, Servicio Cántabro de Salud
• Switzerland
  • Geneve, Switzerland
    • Hospitaux Universitaires de Geneve

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patient with systemic autoimmune diseases

Description

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 Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gene expression in total blood	Gene expression will be done using commercial gene expression microarrays in total blood from all samples using the RNA Paxgene tube.	2 years
Flow cytometry analysis to determine cell proportions in the total blood mixture in all individuals.	9 optimized panels of antibodies will be used to determine cell subpopulations in peripheral blood (including very minor cell populations).	24 hours
Metabolite determination	Metabolite determination in plasma and urine using Nuclear Magnetic Resonance	2 years
Exosome isolation from plasma and urine	set up of the methodology for isolating exosomes in these bodily fluids for gene expression analysis	2 years
Cytokine profile determination	88 different cytokines will be assessed with Luminex	2 years
Gene methylation in total blood	Methylation analysis will be done using the methylome 450k array using the DNA obtained from total blood. MicroRNA gene expression arrays using total blood.	2 years
routine autoantibodies in serum	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.	2 years
Genotyping	Genotyping will be done using a whole genome array	2 years

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza Progreso y Salud
• Collaborators: Karolinska Institutet; Eli Lilly and Company; Medical University of Vienna; Sanofi; Bayer; Charite University, Berlin, Germany; Hannover Medical School; KU Leuven; Institut d'Investigació Biomèdica de Bellvitge; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; University Hospital, Brest; Université Catholique de Louvain; Andaluz Health Service; UCB Biopharma S.P.R.L.; Universidad de Granada; Institut de Recherches Internationales Servier; Szeged University; National Research Council, Spain; University of Milan; University of Geneva, Switzerland; Innovative Medicines Initiative; Centro Hospitalar do Porto; Servicio Cántabro de Salud; Atrys Health; August Pi Sunyer Biomedical Research Institute; Klinikum der Universität Köln; Quartz Bio S.A.; The Cyprus Foundation for Muscular Dystrophy Research

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2014
• Primary Completion (ACTUAL): October 1, 2017
• Study Completion (ACTUAL): October 1, 2017

Study Registration Dates

• First Submitted: August 22, 2016
• First Submitted That Met QC Criteria: August 31, 2016
• First Posted (ESTIMATE): September 7, 2016

Study Record Updates

• Last Update Posted (ACTUAL): May 23, 2018
• Last Update Submitted That Met QC Criteria: May 22, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: SADs; Molecular Reclassification
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases
• Other Study ID Numbers: PRECISESADS CS (RB 14.106)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED